IC is not associated with any specific symptoms. Patients may present with fever, and do not show a favorable response to broad-spectrum antibiotics. Otherwise, symptoms depend on the site of tissue invasion and may correspond to those observed in individuals suffering from:

• Chorioretinitis and endophthalmitis
• Endocarditis
• Meningitis
• Osteomyelitis and spondylodiscitis
• Arthritis or prosthetic joint infection
• Peritonitis

• Fever

  However, the most common symptoms of invasive candidiasis are fever and chills that don’t improve after antibiotic treatment for suspected bacterial infections. [cdc.gov]

  Suspected candidemia: empiric antifungal therapy in the ICU Neutropenic patients with peristent fever after 4-7 days should receive empiric antifungal therapy per published guidelines. [clinicaladvisor.com]

  While in the hospital, she developed symptoms that where not directly associated with her broken bones and cuts, such as a high fever and chills. [study.com]

  The 19-year-old man complained of month-long fever and lower back pain. He also had a history of scalded mouth syndrome. [ncbi.nlm.nih.gov]

• Chills

  However, the most common symptoms of invasive candidiasis are fever and chills that don’t improve after antibiotic treatment for suspected bacterial infections. [cdc.gov]

  While in the hospital, she developed symptoms that where not directly associated with her broken bones and cuts, such as a high fever and chills. [study.com]

  Fever and chills that do not improve after antibiotic therapy are the most common symptoms. [medicinenet.com]

  Invasive candidiasis Specialty Infectious disease Symptoms fever and chills Invasive candidiasis is an infection (candidiasis) that can be caused by various species of Candida yeast. [en.wikipedia.org]

• Nausea

  The most common adverse effects that did not lead to drug discontinuation included mild to moderate abdominal pain, diarrhea, nausea, and vomiting. In total, 2 patients experienced adverse effects related to the study drug. [contagionlive.com]

  Symptoms can include: pain or bloating in your abdomen fever nausea and vomiting feeling tired or fatigued diarrhea diminished appetite In order to diagnose the condition, your doctor will take a sample of abdominal fluid (peritoneal fluid). [medicalnewstoday.com]

  There may be nausea, vomiting, pain in the upper parts of the abdomen etc. Symptoms of Vulvovaginal Candidiasis In women there may be burning, itching and stinging of the vaginal entrance. [news-medical.net]

  You have nausea or are vomiting. Your pain gets worse, even after treatment. You see halos or rainbows around lights. You have questions or concerns about your condition or care. Care Agreement You have the right to help plan your care. [drugs.com]

• Vomiting

  All subjects reported at least 1 treatment emergent adverse event (AE) with diarrhoea (22.9%), vomiting (22.9%) and pyrexia (18.8%) being most frequent. [idsa.confex.com]

  The most common adverse effects that did not lead to drug discontinuation included mild to moderate abdominal pain, diarrhea, nausea, and vomiting. In total, 2 patients experienced adverse effects related to the study drug. [contagionlive.com]

  Symptoms can include: pain or bloating in your abdomen fever nausea and vomiting feeling tired or fatigued diarrhea diminished appetite In order to diagnose the condition, your doctor will take a sample of abdominal fluid (peritoneal fluid). [medicalnewstoday.com]

  There may be nausea, vomiting, pain in the upper parts of the abdomen etc. Symptoms of Vulvovaginal Candidiasis In women there may be burning, itching and stinging of the vaginal entrance. [news-medical.net]

• Dysphagia

  We present a case of invasive candidiasis of a jejunal free flap presenting with dysphagia and a mass. To our knowledge this is previously unreported. [ncbi.nlm.nih.gov]

  Symptoms and Signs Esophageal candidiasis is most often manifested by dysphagia. Candidemia usually causes fever, but no symptoms are specific. [msdmanuals.com]

  Symptoms depend on the site of infection and include dysphagia, skin and mucosal lesions, blindness, vaginal symptoms (itching, burning, discharge), fever, shock, oliguria, renal shutdown, and disseminated intravascular coagulation. [merckmanuals.com]

  Referral Admit to hospital if there are systemic symptoms, the patient is unwell or if there are oesophageal symptoms (dysphagia or retrosternal pain) - particularly if there is immunocompromise. [patient.info]

• Abdominal Pain

  The most common adverse effects that did not lead to drug discontinuation included mild to moderate abdominal pain, diarrhea, nausea, and vomiting. In total, 2 patients experienced adverse effects related to the study drug. [contagionlive.com]

  When symptoms are present, they can include: a burning or painful sensation when urinating an increased need to urinate blood in the urine pelvic or abdominal pain Fungal UTI treatment Treatment is only recommended for people who are showing symptoms. [healthline.com]

  Some women may also experience dysuria (pain felt on urination), superficial dysparenunia (pain felt on penetration during sex) and spotting (typically after sex or outside of normal periods). [doctorflame.com]

  Clinical features are fever (unresponsive to broad-spectrum antibiotics), abdominal pain, tender hepatosplenomegaly, vomiting, dysphagia and jaundice. It may be a form of inflammatory immune reconstitution syndrome. [patient.info]

• Diarrhea

  The most common adverse effects that did not lead to drug discontinuation included mild to moderate abdominal pain, diarrhea, nausea, and vomiting. In total, 2 patients experienced adverse effects related to the study drug. [contagionlive.com]

  Abstract The study aims at evaluating the relation of Candida spp. with diarrhea in children. A cross sectional study was carried out in Kirkuk city from 15th of January 2017 to 15th of June 2017. [iasj.net]

  Symptoms can include: pain or bloating in your abdomen fever nausea and vomiting feeling tired or fatigued diarrhea diminished appetite In order to diagnose the condition, your doctor will take a sample of abdominal fluid (peritoneal fluid). [medicalnewstoday.com]

  Persistent flatulence, burping, bloating, constipation or diarrhea, and stomach cramps may be caused by a lack of healthy bacteria in your digestive tract. [draxe.com]

  Patients with chemotherapy-induced neutropenia accumulate various risk factors: they usually receive wide spectrum antibiotics for several days, they have serious gastrointestinal epithelial tissue dysfunction, usually with diarrhea and signs of mucosal [intechopen.com]

• Retinal Hemorrhage

  In neutropenic patients, retinal hemorrhages occasionally also occur, but actual infection of the eye is rare. [msdmanuals.com]

• Retinal Lesion

  Candidal endophthalmitis starts as white retinal lesions that are initially asymptomatic but can progress, opacifying the vitreous and causing potentially irreversible scarring and blindness. [msdmanuals.com]

• Visual Impairment

  Chronic iritis can also cause serious visual impairment if not treated, iritis can lead to glaucoma or vision loss. If you have symptoms of iritis, see your doctor as soon as possible. [nzherald.co.nz]

• Arthritis

  Diseases include a type of arthritis called ankylosing spondylitis, reactive arthritis, inflammatory bowel disease and psoriatic arthritis. Behcet's disease. [mayoclinic.org]

  Other forms of invasive candidiasis include endocarditis, peritonitis, meningitis, osteomyelitis, arthritis, endophthalmitis. [unboundmedicine.com]

  Sometimes iritis is just one symptom of a disease that affects other organ systems: arthritis and spinal degenerative disease, juvenile rheumatoid arthritis, psoriasis, lupus, and other collagen vascular diseases, bowel disturbances such as ulcerative [ophthalmologyltd.com]

  Diseases include ankylosing spondylitis, reactive arthritis formally known as Reiter's syndrome, inflammatory bowel disease and psoriatic arthritis. Behcet's disease. [nzherald.co.nz]

  Osteomyelitis and fungal arthritis Osteomyelitis is a bone infection while fungal arthritis (also called septic arthritis ) is a fungal infection of a joint. Both conditions can be caused by Candida species, although this is rare. [medicalnewstoday.com]

• Skin Lesion

  Symptoms depend on the site of infection and include dysphagia, skin and mucosal lesions, blindness, vaginal symptoms (itching, burning, discharge), fever, shock, oliguria, renal shutdown, and disseminated intravascular coagulation. [msdmanuals.com]

  May have macronodular skin lesions, candidal endophthalmitis, multi-organ infection or, rarely, septic shock. Characteristic skin lesions may be present in some patients with candidaemia or disseminated candidiasis. [patient.info]

  Careful physical exam–look for skin lesions (biopsy suspicious lesions). Dilated funduscopic exam to look for evidence of candida retinitis. [clinicaladvisor.com]

• Grieving

  Harrison D, Muskett H, Harvey S, Grieve R, Shahin J, Patel K, et al. [ijccm.org]

• Vaginal Discharge

  Vaginitis – Symptoms Common symptoms of vaginitis include vaginal discharge, itch and discomfort. [doctorflame.com]

  Symptoms of Vulvovaginal Candidiasis In women there may be burning, itching and stinging of the vaginal entrance. Sometimes this is accompanied by creamy white cottage cheese like vaginal discharge. [news-medical.net]

  discharge that can be either watery or thick and white an itchy or painful feeling in or outside the vagina or on the penis rash, redness, or swelling around the vagina However, in some cases Candida infections on the penis may cause no symptoms at all [healthline.com]

• Kidney Failure

  Like other types of yeast infections, if you have diabetes, a weakened immune system, kidney failure, or are on antibiotics, your chances of getting it are greater. [webmd.com]

  failure or are on hemodialysis People who have diabetes Last updated: 12/15/2016 Systemic candidiasis is usually suspected in people who have an increased risk of developing an invasive Candida infection and have symptoms of an infection. [rarediseases.info.nih.gov]

  failure shock Diagnosis and treatment Candidemia can be diagnosed when the yeast is isolated from a blood sample. [medicalnewstoday.com]

  As with other yeast infections, an individual’s risk of this infection developing is increased if they have a weakened immune system, are diabetic, suffer from kidney failure or are taking antibiotics. [mymed.com]

• Oliguria

  Some patients develop a syndrome resembling bacterial sepsis, with a fulminating course that may include shock, oliguria, renal shutdown, and disseminated intravascular coagulation. [msdmanuals.com]

  Symptoms depend on the site of infection and include dysphagia, skin and mucosal lesions, blindness, vaginal symptoms (itching, burning, discharge), fever, shock, oliguria, renal shutdown, and disseminated intravascular coagulation. [merckmanuals.com]

Anamnestic data are of major importance to identify patients at risk of IC, since clinical findings are generally non-specific. Furthermore, symptoms triggered by disseminated candidiasis may be masked by those related to comorbidities. Blood samples should be obtained from patients who are suspected to have IC and be sent for blood cultures. Although this approach is considered the gold standard for diagnosis, it yields negative results in case of non-candidemic systemic candidiasis and lacks sensitivity for candidemia. With regards to the latter, molecular biological techniques and immunoassays have increasingly been applied to demonstrate the presence of Candida spp. in blood specimens [8]. Immunoassays are employed to prove the presence of components of the fungal cell wall, namely of mannan and (1–3)-β-D-glucan. Conduction of multiple tests may be required to augment both specificity and sensitivity of the diagnostic workup.

Confirmation of non-candidemic, deep-seated candidiasis is a major challenge. Essentially, available techniques correspond to those described before, i.e., they comprise tissue cultures and detection of Candida antigens by polymerase chain reaction or immunoassays. Neither test yields reliable results with regards to specificity and sensitivity. Moreover, in order to examine tissue cultures, invasive procedures have to be carried out. Histopathologic evidence of invasion is required to distinguish IC from mere colonization with Candida spp. In this line, the presence of blastospores, hyphae or pseudohyphae has to be demonstrated. Diagnostic imaging (e.g., endoscopy, endocardiography) is recommended to assess the involvement of additional organs.

The administration of echinocandins like anidulafungin, caspofungin or micafungin is highly recommended for the initial treatment of IC [9] [10]. Dosage is as follows:

• Anidulafungin: an initial dose of 200 mg followed by daily doses of 100 mg
• Caspofungin: an initial dose of 70 mg followed by daily doses of 50 mg
• Micafungin: daily doses of 100 mg

Most experts also support the use of liposomal amphotericin B (3 mg/kg per day), voriconazole (initially 6 mg/kg per day, subsequently reduction to 3 mg/kg per day) and fluconazole (an initial dose of 12 mg/kg followed by daily doses of 6 mg/kg) in affected individuals. Evidence regarding the efficacy of distinct formulations of amphotericin B and other azoles is at best of moderate quality. Ideally, the final decision on the appropriate antifungal treatment is based on the results of susceptibility testing. In case of candidemia, antimycotic therapy should be continued for a minimum of two weeks after daily blood cultures yield negative results and after resolution of neutropenia and candidemia-related symptoms.

Sole systemic drug therapy is often insufficient to treat deep-seated candidiasis. For instance, intravitreal injection of antimycotic drugs and vitrectomy should be considered in patients with ocular IC. Patients diagnosed with candidal endocarditis should undergo surgery within a few days.

Indwelling catheters and infected prostheses should be removed if at all possible.

IC is still related to mortality rates of 35 to 60% [4]. This is due to the fact that the disease is not usually diagnosed until advanced stages, and this particularly applies to cases not associated with candidemia. Furthermore, drug resistance is a major problem, especially in case of infection with C. glabrata, C. parapsilosis, or C. krusei. Prevalence rates of those species are higher among patients who previously received antifungal therapy. C. parapsilosis is able to form biofilms which render the fungus even more resistant to eradication. Because prolonged hospitalization increases the overall risk of infection, the duration of hospital stay may also be considered an unfavorable prognostic factor.

The etiologic agents of IC are opportunistic pathogens pertaining to a genus of yeast named Candida. Candida spp. are ubiquitously present in the environment and in the microflora of the human body. They are best known for causing cutaneous and vaginal candidiasis (commonly referred to as thrush and vaginal mycosis). Contrary to those entities, IC is associated with an infiltration of usually sterile sites by Candida spp. In sum, more than a dozen Candida spp. have been associated with IC.

The following species are frequently isolated from IC lesions [2]:

• C. albicans
• C. glabrata
• C. parapsilosis
• C. tropicalis
• C. krusei

Fewer case reports exist on IC due to infections with [3]:

• C. lusitaniae
• C. guilliermondii
• C. dubliniensis
• C. kefyr
• C. pelliculosa
• C. famata
• C. rugosa
• C. lipolytica
• C. zeylanoides
• C. inconspicua
• C. lambica
• C. sake

This list is expected to grow as species identification gains importance in IC workup.

While a colonization of skin and mucous membranes is observed in large proportion of severely ill, hospitalized patients, IC is less common [4]. The latter is most frequently diagnosed in patients hospitalized in intensive care units, in those who recently underwent surgery, those who suffer from solid tumors, hematological malignancies, or immunodeficiency due to an infection with human immunodeficiency virus (HIV). Furthermore, transplant patients and those who have a central venous catheter are at higher risks of developing IC. Accordingly, demographic data of IC patients largely reflect the epidemiology of the aforementioned diseases: French researchers have worked with more than 2,400 blood samples obtained from patients with candidemia, the vast majority of whom were adults [2]. Their mean age was 59 years, but specimens have been collected from patients as young as 15 years and as old as 99 years. Males accounted for approximately 60% of pediatric and adult patients. In the United States, overall IC incidence rates of up to 29 per 100,000 inhabitants and 24 per 10,000 hospital discharges have been reported [5]. Similar incidence rates are to be expected elsewhere as no significant geographical differences in the prevalence of Candida infections in patients hospitalized in intensive care units have been demonstrated [6].

The source of pathogens triggering IC has been a matter of intense debate. Candida spp. may colonize human skin and the intestinal tract, and this condition is not typically associated with clinical symptoms. IC develops when fungi spread to other tissues, either from exogenous or endogenous sites. While both routes of infection presumably play a role in IC pathogenesis, available data imply the latter to be more common [7]. However, inoculation of fungi originating from the skin is assumed to account for catheter-related IC. In general, the risk of IC correlates with the prevalence of Candida spp. in either site. Patients hospitalized in intensive care units are generally treated with broad-spectrum antibiotics that may induce changes in species composition of their skin and gut flora, and this may favor Candida overgrowth.

Only upon destruction of the physical integrity of the cutaneous or intestinal mucosal barrier, or in case of functional deficits, can Candida. spp. reach the bloodstream and internal organs. In this context, surgery, especially gastrointestinal surgery, largely facilitates the spread of pathogens. Neutrophil granulocytes are part of the innate immune system and fulfill important functions in controlling yeast infections. But those who are immunodeficient either due to immunosuppressive therapy (to avoid transplant rejection) or due to hematological malignancies or HIV infection , are often neutropenic. Also, lesions of mucous membranes are common in patients receiving cytostatic drugs for cancer.

While the prophylactic use of antifungal compounds may hinder the spread of pathogens colonizing the patient's skin and mucous membranes, it increases the risk of resistance development and increases the prevalence of less susceptible Candida spp. This has been observed in a recent study conducted in France: antimycotic treatment was shown to decrease the prevalence of C. albicans, but at the same time, prevalence rates of C. glabrata, C. parapsilosis and C. krusei increased [2]. Thus, antimycotic prophylaxis should only be given to selected patients, and guidelines have been established to aid the decision on whether a critically ill or immunodeficient patient requires such medication [9] [11]. Briefly, these guidelines consider antifungal prophylaxis for the following patient groups:

• Extremely low-birth weight neonates.
• Severely neutropenic patients who present with fever refractory to broad-spectrum antibiotic treatment.
• Those who recently underwent abdominal surgery and suffer from recurrent gastrointestinal perforations or anastomotic leakages.
• Critically ill patients who recently underwent surgery and who are expected to remain hospitalized in intensive care units for more than three days.
• Patients who are expected to be ventilated for a total of more than five days.

The interested reader is referred to the cited studies, which include more detailed information including the drugs of choice and their dosage.

Alternatively, high-risk patients may be identified by serological markers and score systems [4] [12].

The term invasive candidiasis (IC) describes an infection of physiologically sterile sites of the human body with fungi belonging to the genus Candida. If these pathogens spread hematogenously from the primary site of colonization, patients develop candidemia, which is considered the most common form of IC. Furthermore, IC may refer to non-candidemic systemic candidiasis, and this condition is associated with growth and reproduction of fungi in the abdomen, heart, central nervous system, joints, bones, eyes, and other tissues [1].

IC is primarily a nosocomial infection. Because Candida spp. may colonize the skin and intestinal mucous membranes of humans, any pathology or procedure interfering with the physical or functional integrity of the respective barriers may predispose for Candida dissemination. This mainly concerns critically ill and immunocompromised patients. IC is not associated with any specific symptoms, and although the isolation and identification of Candida spp. in blood and tissue cultures is considered the gold standard for IC diagnosis, these procedures lack sensitivity. Thus, confirmation of IC remains a major challenge. In this context, the identification of risk factors predisposing for IC is of utmost importance to prevent diagnostic delays and to initiate the appropriate treatment as early as possible. Still, about half of IC patients succumb to the disease.

Candidiasis refers to an infection with yeast pertaining to the genus Candida. These opportunistic pathogens are best known for causing thrush and vaginal mycosis, but in these entities, fungi do not invade the bloodstream and do not spread to internal organs. In contrast, invasive candidiasis (IC) describes an infection of physiologically sterile sites of the human body.

Candida species may colonize human skin and the intestinal tract, and this condition is not typically associated with clinical symptoms. However, if the physical and functional integrity of the cutaneous or intestinal mucosal barrier is disturbed, fungi may spread to the bloodstream, to the abdominal cavity, and eventually to the eyes, heart, joints, bones, and central nervous system. Most frequently, this occurs in individuals who recently underwent abdominal surgery, who suffer from solid tumors, lymphoma or leukemia, whose immune system is compromised due to an infection with human immunodeficiency virus or immunosuppressive therapy. Additional known risk factors are prolonged hospitalization in intensive care units and ventilation.

Treatment mainly consists of systemic administration of antimycotic drugs like anidulafungin, caspofungin, amphotericin B or fluconazole. Medication is initially given intravenously, but patients are later given drugs that can be ingested orally. In case the eyes, the heart, or skeleton are affected, patients may need to undergo surgery. Unfortunately and despite provision of optimum therapy, about half of IC patients succumb to the disease. Because of the detrimental consequences of IC, high-risk patients are administered antifungal prophylaxis.

1. Montravers P, Dupont H, Eggimann P. Intra-abdominal candidiasis: the guidelines-forgotten non-candidemic invasive candidiasis. Intensive Care Med. 2013; 39(12):2226-2230.
2. Lortholary O, Desnos-Ollivier M, Sitbon K, Fontanet A, Bretagne S, Dromer F. Recent exposure to caspofungin or fluconazole influences the epidemiology of candidemia: a prospective multicenter study involving 2,441 patients. Antimicrob Agents Chemother. 2011; 55(2):532-538.
3. Pfaller MA, Diekema DJ, Messer SA, Boyken L, Hollis RJ, Jones RN. In vitro susceptibilities of rare Candida bloodstream isolates to ravuconazole and three comparative antifungal agents. Diagn Microbiol Infect Dis. 2004; 48(2):101-105.
4. Eggimann P, Que YA, Revelly JP, Pagani JL. Preventing invasive candida infections. Where could we do better? J Hosp Infect. 2015; 89(4):302-308.
5. Pfaller MA, Diekema DJ. Epidemiology of invasive candidiasis: a persistent public health problem. Clin Microbiol Rev. 2007; 20(1):133-163.
6. Vincent JL, Rello J, Marshall J, et al. International study of the prevalence and outcomes of infection in intensive care units. Jama. 2009; 302(21):2323-2329.
7. Nucci M, Anaissie E. Revisiting the source of candidemia: skin or gut? Clin Infect Dis. 2001; 33(12):1959-1967.
8. Calandra T, Roberts JA, Antonelli M, Bassetti M, Vincent JL. Diagnosis and management of invasive candidiasis in the ICU: an updated approach to an old enemy. Crit Care. 2016; 20(1):125.
9. Cornely OA, Bassetti M, Calandra T, et al. ESCMID* guideline for the diagnosis and management of Candida diseases 2012: non-neutropenic adult patients. Clin Microbiol Infect. 2012; 18 Suppl 7:19-37.
10. Pappas PG, Kauffman CA, Andes DR, et al. Clinical Practice Guideline for the Management of Candidiasis: 2016 Update by the Infectious Diseases Society of America. Clin Infect Dis. 2016; 62(4):e1-50.
11. Tragiannidis A, Tsoulas C, Groll AH. Invasive candidiasis and candidaemia in neonates and children: update on current guidelines. Mycoses. 2015; 58(1):10-21.
12. Mikulska M, Bassetti M, Ratto S, Viscoli C. Invasive candidiasis in non-hematological patients. Mediterr J Hematol Infect Dis. 2011; 3(1):e2011007.