Diagnosis and treatment of invasive Candida infections – a review article

Candida albicans is the most common cause of fungal infections worldwide. Invasive candidiasis comprises candidemia and deep-seated candidiasis. Most yeast invasive infections are endogenous with a high mortality. Pathogenesis of candidiasis depends on avoiding host immune responses, as well as the virulence factors of the fungus enabling colonization and invasion of tissues. Adequate source control and antifungal therapy administered within a short time is critical to get a better prognosis. The emergence of drug resistance and the side effects of currently available antifungals are becoming the major problem in the management of Candida spp. infection. Barchiesi et al. study shows that candidemia is a signiicant source of mor MARTA and/or aqueous and also by blood cultures in endogenous endophthalmitis. Negative cultures do not exclude the diag nosis (36). Early diagnosis and prompt treatment allow to avoid serious complications. Decisions


INTRODUCTION
Invasive fungal infection is associated with a high mortality ranging from 29 to 90% (1). In Europe invasive fungal infections include invasive yeast infections with Candida spp. as the absolutely dominating pathogen (41). Invasive Candida spp. infections are the most common nonmucosal fungal diseases among hospitalized patients in the developed world. Candida spp. is also bidity and mortality. Mortality of candidemia is very high, ranging to 63% depending on the patients population. The elderly population is particularly vulnerable to Candida spp. infections, this can be due to several factors such as: high frequency of comorbidities, aging-related physiological changes, polypharmacy, and high colonization rate (4). Early initiation of effective antifungal therapy is critical in the successful treatment of candidemia. There is much higher mortality rates among patients with candidemia whose therapy was delayed (4).
The identiication of the etiological factor followed by the direct preparation blood cultures is usually negative in the case of disseminated candidiasis, making diagnosis dificult. In the case of candidemia, blood should be collected again after 24 h. In candidiasis or severe organ candidalysis, there should be determined azoles susceptibility (echinocandin susceptibility indicated in previously treated patients and in C. glabrata and C. parapsilosis infection). In candidiasis, it is recommended to repeat blood cultures daily until negative results are obtained (28).
The selection of drug for the treatment of candidemia should optimally take into account any history of recent azole exposure, a history of intolerance to an antifungal agent, the dominant Candida species and current susceptibility data in a particular clinical unit or location, severity of illness, relevant comorbidities, and evidence of involvement of the CNS, cardiac valves, and/or visceral organs (49).
Fluconazole (≥6 mg/kg/24 h) is irst-line therapy for patients who are hemodynamically stable, who have no previous exposure to azoles, and who do not belong to a group at high risk of C. glabrata. Patients with candidemia and suspected concomitant endocardial or CNS candidiasis should receive amphotericin B-AmB in ≥7 mg/kg daily dose (for endocardial or CNS candidiasis) or echinocandin (for endocardial candidiasis). The echinocandins demonstrate signiicant fungicidal activity against all Candida species. Because of their eficacy, favorable safety proile, and very few drug interactions, the echinocandins are favored for initial therapy for patients who have a recent history of exposure to an azole, moderately severe to severe illness (hemodynamically unstable). They are also recommended for patients with allergy or intolerance to azoles or AmB, or high risk of infection with C. krusei or C. glabrata. A short course of intravenous echinocandin therapy (3-5 days) followed by transition to oral luconazole or voriconazole (for C. krusei infection) is recommended by Infectious Diseases Society of America (49).
According to Polish recommendations, preferred treatment includes echinocandins -caspofungin every 24 h, the irst dose of 70 mg, the next 50 mg; or micafungin 100 mg every 24 h; or anidulafungin irst dose of 200 mg, then 100 mg every 12 h (28). Echinocandin is favored as initial therapy for patients with moderately severe to severe disease due to invasive candidiasis, but in the opinion of most experts it should not be used in all episodes (49).
In C. glabrata susceptible to luconazole or voriconazole, voriconazole 400 mg (6 mg/kg) maintenance therapy every 12 h or luconazole 800 mg (12 mg/kg) per maintenance therapy should be used. In supportive therapy for C. krusei candidiasis voriconazole is recommended in standard doses: 400 mg (6 mg/kg) twice daily for 2 doses, then 200 mg (3 mg/kg) twice daily. Treatment should be continued for 14 days after negative blood culture if no organ spreading occurs (28, 49). If it is not dangerous for the patient, intravenous catheter removal is recommended for nonneutropenic patients with candidemia (26,49).
Candidemia in neutropenic patients is associated with acute disseminated candidiasis, a sepsislike syndrome, multiorgan failure, and death. C. tropicalis is particularly virulent in neutropenic patients. Echinocandins are the irst-line option for therapy and have a better safety proile than other agents (1). Duration of therapy for candidemia in neutropenic patients should be 14 days after resolution of attributable signs and symptoms and clearance of the bloodstream of Candida species, provided that there has been recovery from neutropenia (49). Intravenous catheter removal should be considered for neutropenic patients who have persistent candidemia and in whom it is logistically feasible (68). Granulocyte colony-stimulating factor (G-CSF) mobilized granulocyte transfusions  can be considered in cases of persistent candidemia with anticipated protracted neutropenia (49). Chronic disseminated candidiasis can ensue as a complication of candidemia in neutropenic patients despite antifungal therapy.

Empirical treatment for suspected invasive candidiasis
Candida species are an increasing cause of sepsis among nonneutropenic patients receiving intensive care (4,66). Identiication of patients at risk of Candida spp. infections and prompt adequate antifungal treatment and catheter removal could be critical to decrease early mortality (53).
Candida spp. colonization, severity of illness, number of broad-spectrum antibiotic agents used and duration of use, previous surgery (especially bowel surgery), receipt of dialysis, use of central venous catheters, receipt of parenteral nutrition, and length of ICU stay are important risk factors for invasive candidiasis (26). Empirical antifungal therapy is recommended in critically ill patients with risk factors for invasive candidiasis and no other known cause of fever. Echinocandin are preference in hemodynamically unstable patients, in patients previously exposed to an azole, and in those known to be colonized with azole-resistant Candida species. Liposomal amphotericin B-LFAmB and amphotericin B-desoxycholate (AmB-d) are alternatives, but the risk of toxicity is quite big. Empirical therapy with luconazole may be considered in non-critically ill patients who are known to be colonized with azole-susceptible Candida species or who have no prior exposure to azoles (49).
In neutropenic patients LFAmB (3-5 mg/kg daily), caspofungin (70 mg loading dose, then 50 mg daily) or voriconazole (6 mg/kg twice daily for 2 doses, then 3 mg/kg twice daily) are recommended for empirical antifungal therapy (49). Caspofungin has been shown to be as effective as and better tolerated than L-AmB for empirical therapy (65). Alternative agents are luconazole 800 mg (12 mg/kg) loading dose, then 400 mg [6 mg/kg] daily, which is less toxic than amphotericin B, but its usefulness is limited by its relatively narrow spectrum and itraconazole 200 mg (3 mg/kg) twice daily, but it is available only as an oral formulation and has variable oral bioavailability and frequent gastrointestinal adverse effects (5,38,49).
AmB-d is an effective alternative, but there is a higher risk of toxicity than there is with LFAmB.

Chronic disseminated (hepatosplenic) candidiasis
Chronic disseminated candidiasis (CDC) is the syndrome seen after previous bloodstream; it mainly involves the liver, spleen, and occasionally kidneys and other organs. Chronic disseminated candidiasis occurs mostly in patients after profound and prolonged neutropenia, which is more often seen in patients with acute haematological malignancies (53). Candida spp. infection frequently misdiagnosed for the late onset of clinical and radiological manifestations, this kind of complication is much more rare nowadays (46). Clinical symptoms of disseminated candidiasis are usually not characteristic and include: fever, right upper quadrant discomfort, nausea, and elevation of liver enzymes. The symptoms occur following return of neutrophils and persist for a long time unless treatment is initiated (53). Organ changes in the course of candidiasis can be visualized in imaging such as ultrasonography, computed tomography, magnetic resonance imaging or positron emission tomography-CT (15). The diagnosis of probable hepatosplenic candidiasis requires the presence of typical clinical symptoms and imaging indings, as well as an episode of candidemia within the preceding 2 weeks. Biopsy of the hepatic or splenic lesion(s) is not required.
Lipid formulation AmB 3-5 mg/kg/d or echinocandins (caspofungin every 24 h, irst dose 70 mg, next 50 mg or micafungin 100 mg every 24 h or anidulafungin irst dose 200 mg, then 100 mg every 12 h) for several weeks is recommended as an initial treatment. Followed by oral luconazole, 400 mg (6 mg/kg) daily is prescribed, for patients who are unlikely to have a luco-  (49). Duration of pharmacotherapy is unspeciied, usually several months, until the regression has resolved radiographically in order to prevent relapse. Therapy should be continued for a period of immunosuppression, including during chemotherapy. As an additional treatment nonsteroidal anti-inlammatory drugs or corticosteroids for 1-2 weeks can be used in patients with chronic fever (15,53).

Intra-abdominal candidiasis
Intra-abdominal candidiasis is the most common type of deep-seated candidiasis. Intra-abdominal candidiasis occurs: in patients who have had recent abdominal surgery and includes peritonitis, abdominal abscess, and purulent or necrotic infection at sites of gastrointestinal perforation or anastomotic leak. Patients with secondary or tertiary peritonitis and with recurrent gastroduodenal perforation, anastomotic leaks, or acute necrotizing pancreatitis have a high risk to develop intra-abdominal candidiasis with a high mortality rate (5). Intra-abdominal candidiasis encompasses a range of disease manifestations, which are usually not characteristic. Diagnosis is hampered by the lack of speciic clinical signs and symptoms. The clinical signiicance of Candida spp. in cultures of samples from intra-abdominal sites is controversial and blood cultures are often negative. There are limited data on the utility of using surrogate markers (42,43). Because of diagnostic dificulties, empiric antifungal therapy should be considered for patients with clinical evidence of intraabdominal infection and signiicant risk factors for candidiasis, including recent abdominal surgery, anastomotic leaks, or necrotizing pancreatitis (49). The choice of antimycotic should be guided by the Candida species isolated, antifungal susceptibility patterns and local epidemiology. Duration of antifungal therapy depends on response and the adequacy of source control. Source control with adequate drainage and/or debridement is an important part of therapy (32,49).

Candida spp. intravascular infections and endocarditis
Candida spp. endocarditis was previously considered a rare disease. Its incidence is increasing concurrent with the general increase in Candida spp. infections (63). C. albicans and non-albicans Candida species are the cause of infection with a similar frequency. Risk factors of the disease are: cardiac valvular surgery, but other risk factors include injection drug use, cancer chemotherapy, prolonged presence of CVCs, and prior bacterial endocarditis. Symptoms are similar to those of bacterial endocarditis, but large emboli to major vessels are more frequent. Endocarditis should be suspected when a patient with candidemia has persistent fever despite appropriate treatment, or when a new heart murmur, heart failure, or embolic phenomena occur in the setting of candidemia (11). The preferred treatment is AmBLC 3-5 mg/kg/d (with lucytosine 25 mg/kg every 6 h or without lucytosine) or echinocandin (caspofungin 150 mg/d or micafungin 150 mg/d, or anidulafungin 200 mg/d). Treatment can be continued with luconazole 400-800 mg (6-12 mg/kg/d), provided the sensitivity is conirmed. In patients who are in stable clinical status after the disappearance of candidiasis, as well as in the case of infection with a luconazole-resistant strain, voriconazole 200-300 mg (3-4 mg/kg) is recommended every 12 h or posaconazole 300 mg every 24 h after providing conirmed sensitivity. Surgical treatment includes valve replacement and is recommended by Infectious Diseases Society of America. Treatment should be continued for at least 6 weeks after surgery and for a longer duration in patients with perivalvular abscesses and other complications (28, 49). Candida spp. endocarditis has a propensity to relapse.
In case of Candida spp. infections of pacemakers and cardiac deibrillators, the entire device should be removed. Antifungal therapy is the same as that recommended for native valve endocarditis, given for 4-6 weeks depending on whether the infection involves the wires in addition to the generator pocket. The role of antifungal prophylaxis is controversial (9). Septic deep venous thrombosis is a major complication associated with central venous catheterization in intensive care units. Candida species are one of the most common causative organisms. The incidence of Candida spp. infections is increasing, especially in intensive care patients receiving total parenteral nutrition and long-term broad-spectrum antibiotics (6). If it is possible, surgical treatment and catheter removal is recommended. Farmacotherapy includes lipid formulation AmB, 3-5 mg/kg daily, or luconazole, 400-800 mg (6-12 mg/kg) daily, or an echinocandin (caspofungin 150 mg daily, micafungin 150 mg daily, or anidulafungin 200 mg daily) for at least 2 weeks after candidemia (27,49). Adjunctive therapy like systemic anticoagulation or thrombolytic therapy can be useful in some cases (7).

Candida spp. osteoarticular infections
Candida spp. osteoarticular infections is usually a chronic disease in patients with comorbidities and risk factors. hematogenous dissemination is the most common mechanism of infection, but there are some cases of direct inoculation. In adults axial skeleton (spine) is the most common site of inlammation. C. albicans is the predominant pathogen. After identiication a single focus of infection, there should be a search for other sites of involvement (23, 45). Clinical picture and indings on radiographic imaging are usually not characteristic. Candida spp. osteomyelitis should be considered when a patient presents risk factors and pain without previous trauma (29). Diagnosis of Candida spp. osteomyelitis required the presence of yeast cells consistent with Candida species on histopathological or cytopathological examination of bone specimens, or a positive culture for Candida species from a bone sample obtained with a sterile procedure in the setting of concomitant clinical and/or radiographic evidence of infection. First-line treatment is luconazole, 400 mg (6 mg/kg) daily, for 6-12 months or an echinocandin (caspofungin 50-70 mg daily, micafungin 100 mg daily, or anidulafungin 100 mg daily) for at least 2 weeks followed by luconazole, 400 mg (6 mg/kg) daily, for 6-12 months. Lipid formulation AmB, 3-5 mg/kg daily, for at least 2 weeks followed by luconazole, 400 mg (6 mg/kg) daily, for 6-12 months is an alternative recommended treatment. In speciic cases (mediastinitis and sternal osteomyelitis) surgical debridement of bone is needed (27,49).
Candida arthritis is very rare, C. albicans is the form that is isolated most frequently from fungus-infected joints. Candida spp. arthritis usually affects large joints and particularly involves patients who have risk factors (61). Diagnosis is based on the clinical picture and tests of synovial luid and blood. Drainage is necessary to successful therapy of Candida arthritis, if there is a prosthetic device, it should be removed (64). Infectious Diseases Society of America recommended luconazole, 400 mg (6 mg/kg) daily, for 6 weeks or an echinocandin (caspofungin 50-70 mg daily, micafungin 100 mg daily, or anidulafungin 100 mg daily) for 2 weeks followed by luconazole, 400 mg (6 mg/kg) daily, for at least 4 weeks. The alternative drug is Lipid formulation AmB, 3-5 mg/kg daily, for 2 weeks, followed by luconazole, 400 mg (6 mg/kg) daily, for at least 4 weeks (49).

Candida endophthalmitis
Endophthalmitis is an eye infection that may result in permanent loss of useful vision in the affected eye (17). Inlammation usually involves the posterior chamber. Candida species most often cause endogenous infection and are complicated by candidemia. Those infections can be manifested as isolated chorioretinitis or as chorioretinitis with extension into the vitreous, leading to vitritis (36). The most common species is C. albicans (58).
Endophthalmitis is a clinical diagnosis supported by culture of the vitreous and/or aqueous and also by blood cultures in endogenous endophthalmitis. Negative cultures do not exclude the diagnosis (36). Early diagnosis and prompt treatment allow to avoid serious complications. Decisions Infectious Diseases Society of America recommends in all patients with candidemia a retinal examination, performed by an ophthalmologist, within the irst week of therapy in nonneutropenic patients to establish if endophthalmitis is present. For neutropenic patients, it is recommended to delay the examination until neutrophil recovery (49).

Central nervous system candidiasis
There is an increased incidence of invasive mycoses affecting the CNS, causing important morbimortality. Neurocandidiasis is the most frequent opportunistic entity, with widely clinical presentation like: disseminated candidiasis, as a complication of a neurosurgical procedure, especially when an intracranial device is inserted, or rarely as an isolated chronic infection. C. albicans cause most neurocandidiasis. The clinical presentation includes meningitis, microabscesses, macroabscesses, vascular and medullar injury (11,21,47). The initial symptoms of acute meningitis by Candida spp. are indistinguishable from those produced by bacterial infection (fever, headache, neck stiffness, mental status impairment) (55). Central Nervous System Candidiasis should be suspected in every patient with neurological symptoms and signs presenting with one or more of the following: isolation of Candida in cerebrospinal luid (CSF), blood or in any sterile liquid in patient with pleocytosis in the CSF, lack of response in cases of bacterial or tuberculous meningitis in spite of being under suitable treatment (19,55). Neuroimaging in meningitis by Candida spp. can be useful, CT detect the presence of microabscesses and MRI helps to better evaluate microabscesses. Treatment is based on the antifungal susceptibilities of the infecting species and the ability of the antifungal agent to achieve appropriate concentrations in the CSF and brain. Therapy should be continued until all signs and symptoms and CSF and radiological abnormalities have resolved. Liposomal AmB, 5 mg/kg daily, with or without oral lucytosine, 25 mg/kg 4 times daily, is recommended like an initial treatment. Fluconazole, 400-800 mg (6-12 mg/kg) daily, is recommended as the next step. If it is possible, infected CNS devices should be removed (49).

Urinary tract infections due to Candida species
Candiduria is diagnosed on the basis of the presence of Candida yeast in 2 cultures and usually indicating colonization, not infection. Risk factors include diabetes, a catheter in the bladder, and antibiotic therapy (60). Asymptomatic candidiasis does not require treatment, except in immunocompromised patients (neutropenic patients, very low-birth-weight infants <1500 g) or those undergoing invasive procedures in the urinary tract. It usually disappears after removing the catheter from the bladder or ending antibiotic therapy (31). Patients few days before and after urologic procedures should be treated with oral luconazole, 400 mg (6 mg/kg) daily, or AmB deoxycholate, 0.3-0.6 mg/kg daily. Neutropenic patients and very low-birth-weight infants should be treated like for candidemia (49).
Symptomatic Candida spp. cystitis treatment depends on yeast susceptibility. Infectious Diseases Society of America recommends luconazole, 200 mg (3 mg/kg) daily for 2 weeks. For C. glabrata (luconazol-resistant yeast) there is recommended AmB deoxycholate, 0.3-0.6 mg/kg daily for 1-7 days or oral lucytosine, 25 mg/kg 4 times daily for 7-10 days. In case of C. krusei, AmB deoxycholate therapy is shorter (49). If it is possible, bladder catheter should be removed.
Candida spp. pyelonephritis occurs as a consequence of hematogenous spread to the kidneys in a patient who has candidemia. These patients usually are treated for candidemia and have no urinary tract symptoms or signs (21). Symptoms of a pyelonephritis include fever and back pain. Urine diagnostic tests are not helpful in differentiating colonization from infection (30). Radiology imaging of the urinary tract is helpful in deining structural abnormalities like hydronephrosis, abscesses, emphysematous pyelonephritis, and fungus ball formation (33). Pharmacotherapy is similar to that of symptomatic Candida spp. cystitis, and the doses used may be slightly higher. Surgical treatment involves removing an obstacle in urine outlow. In the case of stent or nephrostomy catheters, they should be replaced (28, 49).

CONCLUSION
Recent changes in the aetiology and growing incidence of invasive candidiasis have serious implications for current and future diagnosis, treatment and prognosis. There is a progressive shift in the aetiology of invasive candidiasis from C. albicans to other species of the Candida genus (16). Rise of multiresistant species, such as C. auris or C. glabrata, is a major problem. Invasive candidiasis is divided into candidemia and deep-seated candidiasis. Mortality rate is extremely high in invasive candidiasis: up to 50% in candidemia and even 97% in patients without having adequate source control and antifungal therapy administered within a short time (32). Intervention as a removal of contaminated central venous catheter or drainage of infected material can affect the increase in the effectiveness of treatment (1,48). Blood cultures or other samples taken under sterile conditions remain the gold standard in the diagnosis of invasive candidiasis (49). however, microbiological techniques for early culture-independent diagnosis like germ tube antibodies, mannan antigens and antibodies, detection of 1,3-β-D-glucan, MALDI-TOF and PNA-FISh have a shortened time of the diagnosis (10), but interpretation of speciicity in these studies can be complicated.
Resistance to antifungal therapy observed in some species (C. auris, C. glabrata) is becoming the major problem in the management of Candida spp. infections. Resistance to the echinocandins is uncommon (from 0-1.7%) (51). Primary resistance to luconazole is rare for C. albicans (resistance rate of 1.4%), C. parapsilosis (3.6%) and C. tropicalis (4.1%). C. krusei is intrinsically resistant to luconazole (78.3%), C. glabrata displays reduced dose-dependent susceptibility compared with other Candida species and has a global resistance rate of 15.7% (20). Voriconazole resistance is generally uncommon (20). In total, MARTA DąBROWSKA, MONIKA SIENKIEWICz, PAWEŁ KWIATKOWSKI, hANNA zIELIńSKA-BLIźNIEWSKA, MIChAŁ DąBROWSKI Pobrane z czasopisma Annales C -Biologia http://biologia.annales.umcs.pl Data: 05/03/2021 12:22:00 U M C S 55 38% of echinocandin-resistant C. glabrata isolates is also found to be resistant to luconazole (51). The majority of C. albicans, C. tropicalis and C. parapsilosis isolates are sensitive to amphotericin B. C. lusitaniae strains very often show clinically signiicant resistance to amphotericin B, but the frequency of this phenomenon has not been precisely determined (20). Flucytosine has a high rate of emergence of resistance during monotherapy, so it is usually given in combination with amphotericin B (3). C. auris surpasses all Candida species as the most dificult pathogen to identify and treat. It has demonstrated multidrug resistant properties and the high mortality rate (approx. 68%) (44). The most common side effects of azoles include transient visual disturbances, skin reactions and hepatotoxicity (18). An important side effect of amphotericin B that occurs in almost all patients after prolonged treatment is the impaired renal function. Others include damage to liver function, profound hypokalemia and hypomagnesaemia. The toxicity of amphotericin B signiicantly limits its use. For this reason, lipid preparations of amphotericin B have been introduced, which have less pronounced side effects (40). One of the most important undesirable effects of lucytosine is myelosuppression and hepatotoxicity, therefore its use in hematological indications requires special care. Side effects during treatment of caspofungin are rare, most commonly it is fever, phlebitis, headache (18).