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Candidemia
Introduction
Candida spp are commensal yeasts that are normally found on human skin, in mucosal and intestinal microbiota, and in the mycobiome. Still, these fungi can become pathogenic and opportunistic if the appropriate circumstances are present.[1] The human mycobiome makes up less than 0.1% of the intestinal microbiome, and up to 60% of people can be colonized with Candida spp.[2] Candida spp can become pathogenic when the equilibrium between commensal organisms is disturbed, and risk factors for Candida spp overgrowth and invasiveness are present. Such risk factors include immunosuppression, the presence of central lines, and exposure to antibiotics. Candida spp can cause invasive and deep-seated candidiasis via the dissemination of Candida spp to sterile parts of the body, such as the peritoneum.[3]
Precise global epidemiological data is lacking, but studies from the United States report that candidemia is the fourth most common healthcare-associated bloodstream infection (BSI) and the most common fungal BSI in patients who are hospitalized.[2][4][5] Candidemia is generally defined as the presence of Candida spp in the blood; more precisely, it is defined as the presence of Candida spp in "at least 1 positive blood culture from a peripheral or a central line."[2] Candidemia is associated with poorer patient outcomes, longer hospital stays, and increased healthcare costs—and carries an attributable mortality rate that varies from 35% to 70%.[1][6]
Although C albicans is still the most common Candida species to cause candidemia, there has been an increased incidence of BSI with nonalbicans Candida spp, which have different epidemiology and antifungal susceptibility profiles.[1][7] In addition, the emergence of C auris, presents a novel, multidrug-resistant Candida spp. This changing epidemiology can result in difficulties when selecting the correct antifungal medication, causing delays in treatment, which is associated with poor patient outcomes and higher attributable mortality.[1][8] Managing candidemia should include immediate blood cultures, focus on the prompt selection and administration of appropriate antifungal therapy with adjustment of antifungals when necessary, removal of indwelling vascular devices if possible, documentation of clearing of blood cultures, and ensuring that the candidemia has not seeded remote sites, leading to complications.[9]
Etiology
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Etiology
Candida is a group of budding, white colony-forming yeasts that belong to the subphylum Saccharomycotina.[10] They are commensal yeasts that are present as normal flora in humans on the skin and in mucosal surfaces, such as the gut microbiota, vagina, and mouth. Up to 60% of people are colonized with Candida spp, which is a prerequisite for developing an infection when risk factors exist.[2]
Many Candida species exist, but certain species are most commonly associated with invasive infections.[1] Each Candida spp has unique behavioral properties and virulence, and the epidemiology can differ by country, healthcare system, and host risk factors.[11] Candida albicans is the most common cause of candidemia worldwide, and the other species most commonly associated with invasive infections are C glabrata (renamed to Nakaseomyces glabrata), C parapsilosis, C tropicalis, C krusei (renamed Pichia kudriavzevii), and the recently emerged C auris—whose occurrence is increasing worldwide.[1][8][10]
Epidemiology
Candidemia is a public health concern because it is associated with poor patient outcomes, longer hospital stays, increased healthcare costs, and carries an attributable mortality rate that varies from 35% to 70%.[1][6] Results from a recent study reported the 30-day overall mortality associated with candidemia to be 64%.[12] Candida spp are commensal yeasts that are part of normal human skin, mucosal, intestinal microbiota, and mycobiome, but they can become pathogenic and opportunistic if the appropriate circumstances are present.[1] The human mycobiome makes up less than 0.1% of the intestinal microbiome. Candida spp are a part of this biome, and up to 60% of people can be colonized with Candida spp.[2] Candida spp can become pathogenic when the equilibrium between commensal organisms is disturbed, and risk factors for Candida overgrowth, invasiveness, and translocation of the organism are present. This combination of colonization and the presence of risk factors can lead to invasive and deep-seated candidiasis, which includes candidemia.[3]. Risk factors predisposing one to the development of infection include critical illness, prolonged intensive care unit stay, an indwelling central venous catheter, cancer, transplantation, exposure to antibiotics, abdominal surgery, immunosuppression, malignancy, and total parenteral nutrition.[13][14][15]
In general, complete epidemiological data from all countries, geographic areas, patient populations, and healthcare systems are lacking. Directly comparing data from studies and surveillance systems can be challenging because different definitions for the denominators are used, and incidence rates may fluctuate even within countries and years.[3] Candidemia is one of the most common healthcare-associated BSI globally in at-risk patients, especially in those patients who require intensive care.[13][14][15]
Candidemia is the most common fungal BSI in hospitalized patients in the United States (US) and Europe and is the fourth most common healthcare-associated BSI in the US.[2][4][5] Although C albicans is still the most common Candida species to cause candidemia, there has been a shift in the species distribution of BSI in recent years, and nonalbicans species such as C glabrata, C parapsilosis, and C tropicalis have been more frequently isolated.[16] In the US, C glabrata is the second most common nonalbicans Candida spp to cause candidemia, followed by C tropicalis and C parapsilosis. The group containing nonalbicans Candida spp has emerged as the most frequently isolated species, higher than C albicans.[13][14][17][18] Candida glabrata is the second most commonly reported from the US, Northern Europe, and Australia, while C parapsilosis is the most prevalent nonalbicans species in Latin America, Southern Europe, and Asia.[16][19]
The increasing incidence of BSI with nonalbicans Candida spp is concerning because these Candida spp have different epidemiological and antifungal susceptibility profiles compared to C albicans and can display varied acquired and inherent susceptibility to antifungals.[1][7][20] Resistance to fluconazole, frequently associated with exposure to the drug, has been well-documented in C albicans. Although it is currently low in geographic regions such as the US and other regions, this may change with increased use of fluconazole.[17] The true prevalence of resistance of C albicans to fluconazole is unknown, but increasing resistance to this drug is worrisome because it is the most frequently prescribed antifungal for Candida infections.[17] Certain nonalbicans species, including C glabrata and C parapsilosis, may display higher rates of resistance to fluconazole than C albicans, and C kruzei is inherently resistant to fluconazole.[1][7][20][21] This changing epidemiology can result in difficulties when selecting the correct antifungal medication, causing delays in treatment, which is associated with poor patient outcomes and is attributed to mortality.[1]
A novel species, C auris, first isolated in 2009 in Japan [22] and first reported in the US in 2016,[23] has emerged and is alarmingly spreading in healthcare systems worldwide. This species, which has spread to 47 countries, is highly transmissible and multidrug-resistant.[24] Using whole genome sequencing, C auris has been reported to have spread almost simultaneously to different continents with the emergence of different clonal populations.[25][26] Theories regarding the reasons behind the emergence and rapid spread of C auris include the increasing use of antifungals and antimicrobials, climate change, healthcare worker shortages, and gaps in infection control. What is extremely worrisome is the susceptibility profile of C auris, which is multidrug- and pandrug-resistant.[26] C auris typically displays non-susceptibility to fluconazole and voriconazole, and frequently echinocandins and amphotericin B.[24] In the United States, 90% of C auris are resistant to fluconazole, and 30% against amphotericin B—and the numbers are increasing. Echinocandin-resistant C auris has also been reported and is increasing, which is worrying because echinocandins are the first-line therapy for invasive Candida infections, which include candidemia.[8][26][27]
Pathophysiology
Candida spp are commensal organisms and are normally found in the gastrointestinal, vaginal, oral, and skin microbiomes.[6] Colonization with Candida spp is a prerequisite for developing invasive candidiasis and candidemia. Concomitant risk factors that can lead to candidiasis include those that allow Candida to cross the mucosal or skin barriers, those that allow it to multiply and create biofilms, and those that decrease the ability of the body to fight off infection.[28] These factors include the presence of indwelling vascular catheters, immunosuppression, gastrointestinal surgery (allowing translocation through the intestinal mucosa), exposure to antibiotics, and immunosuppression. Patients receiving peripheral and total parenteral nutrition and lipid emulsions are also at risk for developing candidemia.[28][29][30]
History and Physical
When evaluating any patient, it is paramount that a complete history be obtained that assesses the patient's complaints and provides an understanding of the patient's risk factors for disease. A complete physical examination should be performed on patients, especially when they have risk factors making them vulnerable to serious infections such as candidemia.[9] Candidemia may manifest clinically with nonspecific symptoms and physical findings. Hence, a high index of suspicion is necessary when evaluating patients with risk factors such as immunosuppression, indwelling vascular catheters (eg, port-a-caths), and antibiotic exposure.
Candidemia most frequently occurs in patients who are hospitalized, including those in the intensive care unit, in those who are colonized with Candida spp, and who have risk factors that allow the organism to become invasive by entering their bloodstream. Candidemia is not limited only to the inpatient setting; individuals in the outpatient setting can also develop candidemia, as many aspects of medical care are now performed as outpatients, eg, chemotherapy and indwelling vascular catheter placement. Clinicians should have a high index of suspicion and a low threshold for considering candidemia in patients with immunosuppression, especially those with neutropenia, indwelling vascular catheters, and current or previous intensive care unit stays when they have nonspecific symptoms, such as a simple fever, rigors, dyspnea, confusion, and hypotension.
Physical findings may also be nonspecific, but clinicians need to be vigilant in looking for complications of candidemia. Depending on the cause of candidemia, complications such as right or left Candida endocarditis may occur, and heart murmurs may be present.[9] The site of the indwelling vascular catheters should always be inspected for erythema or frank pus coming from the entry site, pointing towards an infected indwelling device. Patients who develop septic shock may develop multiorgan failure, with or without reversibility. Endocarditis may be right-sided, especially in patients with indwelling vascular catheters; this is frequently associated with valvular destruction that may require valve replacement. Endocarditis, either right or left, can also result in localized embolic phenomena depending on whether it is right or left-sided, and these emboli can go to organs (eg, the lungs, the central nervous system, and kidneys), resulting in end-organ damage. Skin lesions may be present from disseminated candidemia, especially in patients who are neutropenic. Endophthalmitis is another possible complication, and the Infectious Diseases Society of America recommends a dilated retinal examination when candidemia is diagnosed.[6]
Evaluation
The gold standard for diagnosing candidemia is a positive blood culture. If a blood culture is positive for Candida spp, this should always be considered an actual infection and not a contaminant. Two sets of blood cultures always need to be drawn when candidemia (or any other BSI) is suspected, and 1 set should always be drawn through the indwelling vascular catheter if present.[9]
Unfortunately, blood cultures are limited by their poor sensitivity and slow turnaround time. Results from studies have shown that their sensitivity is only 21% to 71%, although sensitivity can be improved by increasing blood volume and drawing blood cultures more frequently.[31] An essential aspect of having the actual yeast grow in a blood culture is that susceptibility testing can be performed by assessing the minimum inhibitory concentration. Antifungal susceptibility testing can guide targeted antifungal therapy and allow for adjustment of appropriate treatment.[9]
Because of the low sensitivity of blood cultures for Candida spp, surrogate markers can also be used to improve diagnostic accuracy. Considering all patient variables, these markers can be considered as supporting evidence when culture results are not yet available in patients at high risk for candidemia. Such markers are Candida mannan antigen, anti-mannan antibodies, and β-d-glucan (BDG).[32][33] They have the advantage of providing faster results but can have high false-positive rates. The BDG can be used as a negative predictive value.[32][34] When evaluating a patient suspected of candidemia, 2 sets of blood cultures should be obtained. A non-culture test (eg, BDG), should also be performed to enhance the diagnostic accuracy.[6]
Treatment / Management
The Infectious Diseases Society of America has published guidelines and recommendations for the diagnosis and treatment of candidemia in an updated executive summary.[9] When evaluating patients with suspected candidemia, 2 sets of blood cultures should be performed, making sure they are also drawn from an indwelling vascular catheter, if present. Early empiric antifungal therapy should be strongly considered in those who are critically ill with risk factors for invasive candidiasis (eg, the infection is suspected or confirmed, with a positive blood culture for Candida spp). The decision to start therapy should be based on clinical suspicion, risk factors, and surrogate markers of candidemia, such as an elevated BDG.[35] During therapy, it is essential to repeat blood cultures weekly to document the clearance of infection. (A1)
Empiric therapy with an echinocandin should be the first choice when suspecting candidemia or when cultures are positive for Candida spp.[36] Fluconazole may be administered in certain patients who are not critically ill and in those whose susceptibility to fluconazole is likely. Deescalate to fluconazole if the patient is stable after 5 to 7 days of echinocandin therapy with negative repeat blood cultures, and if the isolated Candida spp is susceptible to fluconazole.[9] Lipid formulation amphotericin B (AmB) can be given to patients with intolerance to other antifungals, with resistance to fluconazole or echinocandins, or when other antifungals are unavailable.[6] De-escalating from AmB to fluconazole is recommended after 5 to 7 days in stable individuals whose Candida isolates are susceptible to fluconazole, and whose repeat blood cultures are negative.[9] (A1)
If C glabrata is present, higher doses of fluconazole are recommended. Similarly, if other species, such as C parapsilosis, are present, treatment needs to be tailored to resistance patterns because C parapsilosis may be less susceptible to echinocandins. Depending on the patient's condition, initial therapy may need to be altered when titrating to culture results.[6][37] A special mention is necessary for C krusei because it is inherently resistant to fluconazole.(A1)
Initial treatment with an azole should be considered in patients with concomitant meningitis, endophthalmitis, and urinary tract infections (due to low penetrance of echinocandins to these areas) and in patients with prior exposure to echinocandins.[6] Due to the emergence of antifungal resistance in Candida spp and the advent of multidrug-resistant C auris, antifungals should be administered judiciously, with targeted therapy, de-escalation if and when susceptibility results are available, and early discontinuation when no candidemia has been identified.[6][9] Central venous catheters should be removed as soon as possible if they are deemed the source of infection and can be safely removed.[9] The recommended duration of therapy for uncomplicated candidemia is at least 2 weeks, especially after the indwelling catheter is removed and after the candidemia is documented to have cleared.(A1)
Endocarditis needs a special mention. In the case of native valve endocarditis, a valve replacement is recommended, and treatment duration is for 6 weeks after the valve replacement, and even longer if there is a perivalvular abscess. Chronic suppression with an antifungal is recommended if the valve cannot be replaced. For prosthetic valve endocarditis or pacemaker endocarditis, removing the hardware is suggested, and 6 weeks of therapy is recommended after the removal. Chronic suppressive therapy should be considered on a case-to-case basis. Infection of the pacemaker pocket alone requires 4 weeks of antifungal therapy.[2][6] (A1)
Differential Diagnosis
The differential diagnosis of candidemia includes the following:
- Ascending cholangitis
- Bacterial meningitis
- Bacterial sepsis
- Bacterial endocarditis
- Chronic granulomatous disease
- Cholecystitis
- Graft-versus-host disease
- Granulomatous hepatitis
- Hepatic abscess
- Tuberculosis
Prognosis
Candidemia is a public health concern because it is associated with poor patient outcomes, longer hospital stays, increased healthcare costs, and carries an attributable mortality rate varying from 35% to 70%.[1][6] Results from a recent study reported the 30-day overall mortality associated with candidemia to be 64%.[12]
Complications
Physical findings may be nonspecific, but clinicians need to be vigilant in ensuring there are no candidemia complications. Depending on the cause of candidemia, complications such as right or left Candida endocarditis may occur, and heart murmurs may be present.[9] The site of the indwelling vascular catheters should always be inspected for erythema or frank pus coming from the entry site, pointing towards an infected indwelling device. Patients who develop septic shock may develop multiorgan failure, with or without reversibility. Endocarditis may be right-sided, especially in patients with indwelling vascular catheters, and this is frequently associated with valvular destruction that may require valve replacement.
Endocarditis, either right or left, can also result in localized embolic phenomena depending on whether it is right or left-sided, and these emboli can go to organs, eg, the lungs, the central nervous system, and kidneys, resulting in end-organ damage. Skin lesions may be present from disseminated candidemia, especially in neutropenic patients. Endophthalmitis is another possible complication, and the Infectious Diseases Society of America recommends a dilated retinal examination when candidemia is diagnosed.[6]
Consultations
Patients who develop candidemia usually have 1 or more risk factors, including the presence of indwelling catheters, immunosuppression, antimicrobial use, intestinal mucosal surgery or breakdown, and an intensive care unit stay. These patients frequently have multiple comorbidities, are extremely ill, and require consultations by various specialists. Intensive care, internal medicine, and infectious disease clinicians should be managing the treatment. Consulting infectious disease clinicians (for patients with fevers who are in the intensive care unit) has been shown to decrease mortality, is associated with earlier selection of empiric or targeted antifungal therapy, provides better identification and control of the infectious source, and earlier removal of indwelling central lines when compared to patients without an infectious disease consultation.[38][39]
Pearls and Other Issues
Antifungal prophylaxis is well-evidenced in patients who are neutropenic with hematological or solid organ transplantation, whereas prophylaxis with antifungals to prevent candidemia is not routinely recommended in those who are non-neutropenic and critically ill; the supporting evidence, however, is weak.[40][41] Antifungal prophylaxis should be considered in the intensive care unit for select patients who are at the highest risk for candidemia, such as individuals with recurrent gastrointestinal perforations, anastomotic leakage, and small bowel or pancreas transplants.[42]
Enhancing Healthcare Team Outcomes
Candidemia is a serious infection with a high mortality that must be managed promptly. The presence and involvement of an interprofessional team that includes an infectious disease physician, an intensivist, a microbiologist, intensive care nurses, and a pharmacist is necessary to manage all aspects of the patient's care. Patients can become quite ill, with persistent candidemia and complications such as septic shock, and the smooth collaboration of all the healthcare professionals is paramount.[43][44]
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Level 2 (mid-level) evidence