Coping with Candida Infections Scott E. Evans Department of Pulmonary Medicine, University of Texas M. D. Anderson Cancer Center, Houston, Texas

Although Candida spp. exist as normal flora on much of the human body, life-threatening invasive infections by these organisms have increased in recent decades. Candida spp. are now one of the most common causes of nosocomial blood stream infections worldwide, and patients with critical illness or malignant disease demonstrate particular susceptibility. Risk factors are identifiable for virtually all patients who develop invasive candidiasis, and clinicians must maintain vigilance for Candida infections in the appropriate clinical context, given the attributable mortality. This review addresses the clinical and molecular epidemiology of invasive Candida infections, common clinical manifestations, available diagnostic methods, and current recommendations for initial therapy. Keywords: Candida; invasive candidiasis; immunocompromised host; blood stream infections

Typically existing as unicellular yeasts, Candida spp. are normal flora of the human skin, oropharynx, lower gastrointestinal tract, and genitourinary system (1, 2). This normally commensal relationship can be perturbed by host and/or environmental factors to promote infection. Superficial disease, such as oral thrush or dermatitis, can be a source of tremendous patient discomfort. Further, invasive candidiasis, a collective term denoting deep tissue infection, is associated with worsened patient outcomes, increased healthcare resource use, and management difficulty. The incidence of deep Candida infections, especially among immunocompromised patients, has increased in recent decades, as has the proportion of organisms resistant to antifungal therapy (3–7). A recent systematic review identified the attributable mortality for invasive candidiasis to be between 5 and 71% (8), with expert opinion suggesting the actual figure to be around 15 to 25% for adults (1). No matter where in this range the exact figure falls, with an estimated 63,000 episodes of invasive candidiasis per year in the United States (9), invasive candidiasis contributes to many thousands of deaths annually. Studies using microsatellite markers reveal that invasive disease typically arises from endogenous sources (i.e., colonization) rather than de novo exposure to Candida spp. (10), most often from the skin or gastrointestinal tract (2). There appear to be three critical elements in the pathogenesis of invasion: colonization, disruption of mucosal barrier defenses, and immune dysfunction. Studies have attempted to correlate the burden of Candida colonization, defined by the number of sites colonized or the organism counts at a single site, with the risk for development of invasive infection. Whether such quantification is predictive remains uncertain. However, the absence of colonization at clinically relevant sites strongly suggests the absence of invasive candidiasis (4, 11–15).

(Received in original form July 23, 2009; accepted in final form October 20, 2009) Correspondence and requests for reprints should be addressed to Scott E. Evans, M.D., University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Unit 1100, Houston, TX 77030. E-mail: [email protected] Proc Am Thorac Soc Vol 7. pp 197–203, 2010 DOI: 10.1513/pats.200907-075AL Internet address: www.atsjournals.org

Invasive candidiasis has been called a disease of medical progress (1), because its increased incidence in recent decades has paralleled technological healthcare advances. Perhaps most significant among these secular trends is the widespread use of broad-spectrum antibiotics, promoting colonization through alteration of patients’ microbiomes and through pressures on the hospital environment. Medical progress has also contributed to barrier disruption and immune impairment. Candida spp. can gain access to deep tissues via trauma or surgery or via mucositis caused by radiation or chemotherapy. Indwelling intravascular devices breach the skin defenses and provide an attachment site for the fungus because Candida spp. can adhere to plastic or acrylic surfaces. Cytotoxic and immunosuppressive therapies promote dissemination of Candida spp. through induction of cytopenias and/or immune cell dysfunction. Congruent with these pathogenic mechanisms, certain patient populations face uniquely elevated risk for invasive candidiasis, and risk factors are identifiable for nearly all patients who develop deep infections. More than half of all cases occur in patients receiving care in the intensive care unit (ICU) (11, 16–19). As discussed below in the context of candidemia, specific interventions further raise the risk of invasive disease, but the most important risk factor for intensive care–related infections is the ICU length of stay. Studies to determine the effectiveness of antifungal prophylaxis in critically ill patients suggest that Candida colonization rates precipitously increase after 8 days in the ICU, followed by a peak risk of infection at around 10 days in the ICU (20, 21). The other patient population that is conspicuously associated with invasive Candida infections includes individuals with neoplastic disease, including solid tumors and hematologic malignancies. Cancer-related surgeries (especially abdominal) and immune dysfunction related to the underlying disease and its treatment place this group at significantly elevated risk, independent of their use of ICU services. Neutrophil defects, in particular, render patients unable to clear mucosal infections and allow dissemination of invasive disease. On the other hand, isolated T-cell deficiencies promote mucocutaneous infections but less frequently result in invasive candidiasis (22). Thus, patients with HIV disease and other severely immunocompromising conditions present relatively less often with invasive candidiasis than do patients with cancer.

CANDIDEMIA Isolation of Candida spp. from blood cultures is the form of invasive candidiasis most frequently encountered in clinical practice, possibly accounting for 50 to 70% of all deep infections (1). Of these episodes, an estimated 33 to 55% occur in the ICU (4) and are associated with significantly worsened outcomes. Regardless of the causative strain, adults with candidemia in the ICU are estimated to face a nearly 15% increase in mortality, more than 10 additional hospital days, and increased hospital charges of almost $40,000 per episode (4, 19). Candidemia encompasses a range of clinical conditions, from reversible intravascular catheter contamination to life-threatening sepsis. However, because Candida spp. are never normal flora in the blood and, because the clinical trajectory of a patient with

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candidemia is difficult to predict (23, 24), all positive cultures should prompt aggressive antifungal intervention. This includes pharmacotherapy (23, 25, 26) and removal of potentially contaminated catheters and devices (27–29) as appropriate. Candida spp. are the fourth most common cause of nosocomial bloodstream infections in North America and have a higher crude mortality rate than any form of bacteremia, including the most common nosocomial bloodstream pathogen, Staphylococcus aureus (30–33). Further complicating the care of these patients, a recent study of 372 candidemic patients found that 27% had polymicrobial infections, 24% had synchronous bacteremia, and 3% grew more than one Candida spp. (33). Candidemia can affect a broad range of hospitalized patients, including those without neutropenia or severe immunocompromise (30). Although ICU length of stay is most closely correlated with development of candidemia, recent data indicate that approximately 10% of patients in the ICU are at specifically elevated risk for candidemia based on the presence of a central venous catheter or systemic antibiotics for four or more days and two or more of the following risk factors: (1) total parenteral nutrition on Days 1 through 4 of ICU stay, (2) any dialysis on Days 1 through 4 of ICU stay, (3) any major surgery in the 7 days before ICU admission, (4) pancreatitis in the 7 days before ICU admission, or (5) systemic steroids or other systemic immunosuppressive agents in the 7 days before ICU admission (18). Other risk factors include exposure to broad-spectrum antibiotics, diabetes mellitus, any surgery requiring general anesthesia, acute renal insufficiency, solid organ or stem cell transplantation, and mucosal colonization with Candida spp., especially if multifocal (1, 4, 18). As much as 80% of candidemia arises from or in the presence of a vascular access, including central venous catheters, hemodialysis catheters, peripherally inserted central catheters, and implanted ports (34). Features suggesting a noncatheter source include disseminated infection, prior chemotherapy, corticosteroid therapy, and poor response to antifungal therapy (35). Blood cultures are often positive for Candida sooner when arising from a catheter source, and a time-to-positivity greater than 30 hours may help exclude intravascular devices as the cause of candidemia (34). Of more than 150 species of Candida, only about 15 cause human disease (1). Recent epidemiologic evidence shows that Candida albicans remains the most common cause of candidemia in the United States and Europe, though non-albicans species have increased in frequency in recent decades to account for 40 to 50% of cases (9, 10, 30, 32). The mortality rate from bloodstream infection due to non-albicans strains is at least as high as that caused by C. albicans (36, 37). In the United States, C. glabrata is the most common nonalbicans species, especially among immunocompromised patient populations (9). This is particularly relevant given the azole resistance of C. glabrata. C. glabrata infections are often associated with recent surgery, the use of urinary or vascular catheters, solid tumors, and lymphoma (36, 37). The incidence of C. parapsilosis candidemia trails that of C. glabrata in the United States but may have surpassed it in Europe, and this pathogen is now the most common nonalbicans species in Latin America (4, 10). This pathogen is most often identified among patients with intravascular catheters, prosthetic devices, stem cell transplants, and a history of intravenous drug use and among in neonates (36). C. tropicalis is the fourth most common cause of candidemia and is often associated with leukemia, prolonged neutropenia, stem cell transplantation, high APACHE scores in patients with cancer, and prolonged ICU stays (36). C. krusei candidemia is associated with azole prophylaxis, neutropenia, and stem cell transplantation. C. lusitaniae infec-

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tions are typically seen in patients with stem cell transplantation or prior exposure to amphotericin B. C. rugosa has been associated with burn wounds and nystatin prophylaxis. Cancer and stem cell transplantation have been identified as risk factors for candidemia with C. guilliermondii (36).

CANDIDA PNEUMONIA Controversy surrounds the incidence, and even the existence, of Candida pneumonia. Although Candida spp. are often isolated from bronchial washings, tracheal aspirates, and bronchoalveolar lavage samples from patients, documentation of lung parenchymal invasion is infrequent. Because Candida is part of the normal flora for the oropharynx and gastrointestinal tract, growth of Candida from respiratory samples is frequently disregarded as a contaminant, though lower respiratory tract colonization appears quite common (7, 12, 38, 39). The two reported manifestations of Candida pneumonia (40, 41) are (1) pneumonia that follows aspiration of Candida-laden secretions (primary pneumonia) (42) and (2) pneumonia that follows hematogenous Candida dissemination (secondary pneumonia) (5, 43). As with many other fungal pneumonias, the ‘‘gold standard’’ for diagnosis is the histopathologic demonstration of Candida invasion of the lung; however, many of the risk factors that result in susceptibility to the infection often preclude the ability to routinely biopsy these patients. The few available studies indicate that Candida invasion of lung parenchyma is seen in no greater than 0.2 to 8.0% of at-risk ICU patients and cancer patients (12, 42, 44), and a recent prospective study found no cases of tissue invasion in 77 ICU patients with Candida isolated from respiratory secretions (39). However, although all extant data suggest that Candida pneumonia is rare, when present in immunocompromised or critically ill patients, it is associated with considerable mortality (42). Unfortunately, there are no guidelines to differentiate colonization from infection based on bronchoalveolar lavage cultures (7, 45). Consequently, lower respiratory tract cultures from which Candida is recovered must be considered in light of the patient’s risk for infection and the presence of colonization or infection of other sites. A CT scan of a patient with suspected Candida pneumonia is shown in Figure 1. Colonization of the lower respiratory tract (without tissue invasion) is independently associated with increased hospital mortality (38). The mechanisms underlying this observation are unclear, but one potential explanation is that Candida-related immune dysfunction enhances susceptibility to other respiratory pathogens. This hypothesis is supported by the finding that mechanically ventilated patients with Candida colonization display enhanced susceptibility to Pseudomonas ventilator-associated pneumonia (46). Although one may speculate that the Candida colonization and Pseudomonas infections follow the same immune dysfunction, recent laboratory investigations reveal that C. albicans exposure impedes alveolar macrophage reactive oxygen species production and correlates with increased P. aeruginosa pneumonia prevalence in rats (47).

OTHER SITES OF INFECTION Candida infections can present in myriad ways (Table 1). Acute disseminated candidiasis typically occurs in the setting of severe immunocompromise, especially chemotherapy-related neutropenia, and is most often associated with documented candidemia and multiorgan involvement (48). A palpable erythematous or hemorrhagic rash, consistent with small vessel vasculitis, is a characteristic finding (1).

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Figure 1. Suspected Candida pneumonia. A 30-year-old woman with Hodgkin disease presented with fever, hypoxemia, brown sputum production, and dyspnea. New infiltrates were apparent on CT examination (shown). Bronchoalveolar lavage specimens grew only C. albicans. She was successfully treated with fluconazole and broadspectrum antibacterials and was discharged from the hospital no longer requiring supplemental oxygen. Despite the culture results, Candida pneumonia cannot be confirmed without demonstration of fungal tissue invasion.

Candida infective endocarditis is an uncommon, often fatal complication in patients with chronic intravenous catheters or large-caliber hemodialysis catheters. Candida accounts for more than two thirds of fungal endocarditis and is associated with higher mortality than nonfungal causes of infective endocarditis (49). Other risk factors for Candida endocarditis include an abnormal native valve, a prosthetic valve, congenital cardiac abnormalities, and injection drug use. Any valve may be involved, and large vegetations may be associated with systemic emboli (49). Candida infection of ventricular assist devices is similarly described (50). Candida endophthalmitis is a sight-threatening infection that has historically been reported to occur in up to 28 to 45% of patients with untreated candidemia (51, 52), though contemporary reports suggest that the current incidence and the severity of ocular involvement are significantly lower in patients receiving early antifungal therapy for candidemia, with chorioretinitis likely demonstrable in fewer than 10% of patients (1, 51). Even when fundoscopic findings exist, the large majority of patients remains free of eye symptoms (16). Nevertheless, given the potential for blindness and the association of endophthalmitis with Candida-related mortality, at least one formal ophthalmologic examination by an expert should be performed for patients with candidemia (51, 52). This should occur when candidemia is controlled so that subsequent eye involvement is unlikely and after neutrophil counts have recovered in neutropenic patients. Among patients who survive an episode of candidemia, vertebral osteomyelitis (often with diskitis) is a later complication. Patients typically present with progressive low back pain in the absence of fever weeks to months after the episode. Occasionally, this represents the first indication of a previously unrecognized episode of candidemia (1). Chronic disseminated candidiasis, also known as hepatosplenic candidiasis, occurs in patients who have survived candidemia (sometimes unrecognized) while neutropenic. After recovery of their neutrophil counts, patients present with fever; right upper quadrant pain; splenomegaly; liver function test derangements; and focal, sometimes calcified, lesions of the liver, spleen, and kidneys. The widespread use of fluconazole has significantly decreased the incidence of this presentation (53). Candida spp. also cause peritonitis, pyelonephritis, myositis, meningitis, tenosynovitis, septic arthritis, and abscess formation in the abdomen, brain, kidneys, and heart (54). Because of the proclivity for infectious metastases and the influence such

metastases may have on treatment, a comprehensive, systematic evaluation should be undertaken for any patient with unifocal or multifocal invasive candidiasis.

DIAGNOSIS Delayed initiation of anti-Candida therapy is independently associated with mortality (55, 56), but rapid and accurate means for detecting candidemia and invasive candidiasis remain elusive. Currently available techniques present clinicians with insensitivity, false-positive results, and delayed availability of results until it is too late to guide therapy (57, 58). Blood culture positivity is the hallmark of candidemia. However, only about half of the cases of autopsy-proven candidemia are detectable by blood cultures antemortem (57, 58). Furthermore, because treatment of candidemia must be initiated within 12 to 24 hours of drawing the blood culture to improve the outcomes (55), the minimum time necessary for detection using blood cultures is often too long (58). The inadequate performance of blood cultures in the critical setting of invasive candidiasis has prompted enthusiasm for TABLE 1. COMMON SITES OF CANDIDA INFECTIONS Superficial candidiasis Candida dermatitis (intertrigo, diaper rash, balanitis) Candida epiglottitis Candida esophagitis Candida paronychia Chronic mucocutaneous candidiasis Oropharyngeal candidiasis (thrush) Vulvovaginal candidiasis Invasive candidiasis Acute disseminated candidiasis Candida endocarditis Candida endophthalmitis Candida mediastinitis Candida meningitis Candida myositis Candida peritonitis Candida pyelonephritis/urethral candidiasis Candida pneumonia Candida septic arthritis Candida tenosynovitis Candida osteomyelitis Candidemia Chronic disseminated candidiasis Deep tissues abscesses (abdomen, brain, heart, kidneys)

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nonculture-based methods of Candida surveillance. Among these, detection of the fungal cell wall component (1/3)b-D-glucan has perhaps shown the greatest promise for rapidly identifying candidemia. Recent studies reveal a sensitivity of 57 to 100% and a specificity of 44 to 100% in patients suspected of having invasive candidiasis (10, 57–59). This technique may be particularly useful for detecting catheter-related infections because b-glucan is released in large quantities in biofilms (58). Specificity is limited by b-glucan contamination of some antibiotics and medical materials, such as surgical gauze (10), and complementary techniques are required to distinguish invasive aspergillosis from candidemia (58). Given these considerations, some groups have investigated the role of routine b-glucan monitoring in the ICU, rather than its diagnostic use only when candidemia is suspected, with mixed results (57). Diagnostic strategies based on detection of Candida mannan antigenemia and anti-Candida antibodies have also been described. Although C. albicans indirect immunofluoresecent antibody (IFA) IgG is reported to allow detection of passage through the tissue-invasive mycelial stage, all current antigen detection techniques are limited by rapid antigen clearance and antimannan antibodies (10, 57, 58). Polymerase chain reaction (PCR) techniques have also been investigated. Although PCR can detect fungal DNA in a matter of hours and can even determine the species, issues of false-positive results remain, and no PCR tests have been approved for the diagnosis of invasive candidiasis.

MANAGEMENT Delayed initiation of therapy for invasive candidiasis results in considerably increased attributable mortality (11, 55, 56), so it is imperative that clinicians be prepared to promptly and appropriately intervene in suspected and confirmed invasive candidiasis (23, 25, 60). However, due to the often uncertain or delayed diagnosis of invasive candidiasis, clinicians have sought antifungal strategies that will benefit high-risk patients before isolating Candida from a clinical specimen. Prophylaxis involves the application of antifungal treatments to a population, independent of individual patient risk factors (61). This practice appears to be beneficial in prolonged neutropenia, for preterm infants, and probably among liver transplant patients but is discouraged among less selected groups (16). The routine use of fluconazole prophylaxis in the ICU may reduce the number of fungal infections, but it is not routinely recommended due to associated increases in azoleresistant candidemia (2). Preemptive therapy is the early addition of antifungal treatment to individuals with strong risk factors (most notably, intensive colonization). Pursuing the observation that invasive Candida infections follow colonization, Pittet and colleagues reported that colonization intensity (the number of colonized sites corrected for semiquantitative culture results) could identify critically ill surgical patients who would benefit from preemptive antifungal therapy (15). Leo´n and colleagues subsequently incorporated multifocal colonization and other risk factors into a ‘‘Candida score’’ that they found discriminated nonneutropenic critically ill patients who would benefit from early antifungal therapy from those who would not (13, 14). In contrast to preemptive therapy, empiric therapy is antifungal treatment of patients with risk factors for Candida infection who have already developed clinical features of infection possibly due to fungi but in whom there is no microbiologic documentation of infection (61). Undocumented Candida infections are commonly suspected when febrile patients in the ICU fail to improve with broad-spectrum antibac-

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terial therapy, particularly if they have other risk factors for candidemia (54). Due to the correlation of timely treatment and survival (11, 55, 56), empiric initiation of therapy is broadly endorsed for neutropenic and nonneutropenic patients suspected of having invasive candidiasis (23, 25, 26). However, there are much less clinical data to guide the management of unproven infections (62), and the empiric treatment of all highrisk ICU patients with fluconazole has not been shown to improve outcomes (63). Thus, the clinician must maintain vigilance for invasive candidiasis and promptly initiate therapy while seeking a definitive diagnosis. Antifungal drugs licensed for the treatment of suspected or documented invasive candidiasis include polyenes (amphotericin B deoxycholate and lipid formulations of amphotericin B), azoles (fluconazole, itraconazole, and voriconazole), and echinocandins (caspofungin, micafungin, and anidulafungin). Recent years have seen several large trials intended to identify the optimal initial antifungal pharmacotherapy for invasive disease. Three randomized (64–66) and two nonrandomized (28, 67) trials compared fluconazole with amphotericin B or with amphotericin B plus fluconazole for invasive candidiasis (mostly candidemia). Collectively, the fluconazole-only groups demonstrated noninferiority in terms of mortality and experienced fewer serious side effects when compared with the amphotericin B–containing groups. A subsequent open-label study (68) comparing initial therapy with voriconazole or amphotericin B followed by fluconazole found similar response rates at 12 weeks. A comparison of caspofungin to amphotericin B for invasive candidiasis revealed superiority in treatment success and side effects, especially for non-albicans candidemia (69). A trial comparing micafungin with amphotericin B for invasive candidiasis resulted in similar success rates in the two groups but fewer adverse events in the micafungin group (70). A head-tohead comparison of anidulafungin to fluconazole for initial therapy of invasive candidiasis demonstrated significantly better success rates for anidulafungin (71). These data support the use of fluconazole, an amphotericin B formulation, an echinocandin, or the combination of fluconazole and amphotericin B as initial pharmacotherapy for invasive candidiasis. Voriconazole is also approved for first-line therapy of candidemia, although the Infectious Disease Society of America clinical practice guidelines (23) recommend its use primarily as step-down oral therapy for C. krusei or susceptible C. glabrata infections. The choice among these agents depends on the clinical status of the patient, the identified species and its antifungal resistance profile, relative drug toxicity and any preexisting organ dysfunction, and the patient’s prior therapy with antifungal agents. Several groups have published guidelines upon which to base initial empiric therapy decisions for specific patient populations (16, 23, 25, 26, 72), although there is not unanimity regarding initial selections. Among clinically stable, nonneutropenic patients with suspected invasive candidiasis and without prior azole exposure, fluconazole (400 mg/d or z6 mg/kg/d) is an excellent first-choice agent (16, 23, 25, 72). For clinically stable, nonneutropenic patients with prior azole exposure, an echinocandin is an appropriate empiric choice (23, 25). Echinocandin options include caspofungin (70 mg loading dose on Day 1, then 50 mg/d), micafungin (100 mg/d), or anidulafungin (200 mg on Day 1, then 100 mg/d). An echinocandin is also appropriate initial therapy for clinically unstable, nonneutropenic patients suspected of having invasive candidiasis (23, 25), although other potential options include amphotericin B deoxycholate (0.6–1.0 mg/kg/d), a lipid formulation of amphotericin B (3–5 mg/kg/d), high-dose fluconazole (800 mg/d), or a combination of high-dose fluconazole and amphotericin B.

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Current empiric treatment recommendations for neutropenic patients suspected of having candidemia center on the use of echinocandins (caspofungin, micafungin, or anidulafungin; same dosing as above) (23), though some experts advocate amphotericin B deoxycholate or a lipid formulation of amphotericin B in the absence of sepsis (72). Among very stable neutropenic patients without prior azole exposure, high-dose fluconazole may be an acceptable alternative. Voriconazole has also been proposed as an alternate choice if additional mold coverage is desired (23). Local epidemiological data must be considered in empiric treatment decisions. Independent of the patient’s exposure to azoles, when the local incidence of non-albicans Candida blood isolates exceeds 10%, an initial therapy other than fluconazole, such as an echinocandin, should be considered due to the higher incidence of fluconazole resistance in these species. Similarly, hospitals that frequently use fluconazole prophylaxis may benefit from using non-azole agents for empiric treatment due to the risk of fluconazole-resistant C. albicans. Although many cases of invasive candidiasis are suspected but never documented, therapy is ideally guided by the culture of a pathogen from the blood or other sterile site because this enhances the clinician’s ability to predict antifungal efficacy. Fluconazole remains the most common selection for the treatment of infections with C. albicans, C. tropicalis, C. lusitaniae, and C. parapsilosis. C. glabrata and C. krusei are most often managed with an echinocandin or an amphotericin preparation. Although antifungal susceptibility can often be predicted based on the species cultured, individual isolates may not obey the general susceptibility patterns of the species. Therefore, there is an increasing trend toward treatment directed by the documented susceptibility profile of a patient’s isolate. Due to a low incidence of antifungal resistance, data-driven guidelines recommending routine susceptibility testing of C. albicans isolates do not exist. However, expert opinion supports routine susceptibility testing for Candida cultured from patients in the ICU (16), for C. glabrata isolates from blood and sterile sites (23), and for other Candida species that fail to respond to therapy or in which resistance is suspected (23). Documentation of antifungal susceptibility can also facilitate the transition of patients from intensive intravenous therapies to appropriate oral fluconazole or voriconazole as clinical stability is achieved. In general, once a tailored regimen is established, it is recommended to continue treatment for at least 2 weeks after the last positive blood culture (23, 25, 26). In addition to pharmacotherapy, central venous catheters should be removed in the setting of candidemia whenever possible. The data supporting this recommendation are strongest for nonneutropenic patients (27–29). Catheter removal no later than 72 hours after onset has been shown to improve response to antifungal therapy in patients with catheter-related candidemia (35) and is associated with reduced mortality, especially among nonneutropenic patients (27–29, 73). If central venous access is mandatory for patient care, a new site should be obtained rather than changing over a guide wire.

SUMMARY Candida spp. cause severe life-threatening illness in many populations. Recent decades have witnessed increasing disease incidence, shifting molecular epidemiology, and some limited progress in diagnostic techniques. Although the discernment of colonization from infection remains difficult in many situations, clinicians possess several agents with which to aggressively treat invasive disease.

201 Conflict of Interest Statement: S.E. has received reimbursement for serving on an advisory board with Genentech ($1001–$5000). He has patents received or pending with Pulmotect and stock ownership or options with Pulmotect (up to $1000). He has also received funding from noncommercial entities, NIH ($100,001 or more) and Leukemia Research Foundation ($50,001–$100,000).

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