Candidaemia and Invasive Candidiasis
Also known as: Candidemia and Invasive Candidiasis, Candidemia, Bloodstream Candida Infection
Candidaemia is the isolation of Candida from one or more blood cultures. Invasive candidiasis is the wider term, covering candidaemia and deep tissue infection.
Some invasive candidiasis has negative blood cultures: intra-abdominal candidiasis, hepatosplenic candidiasis, and endogenous endophthalmitis. Any positive blood culture is regarded as real infection and never as a contaminant, because skin or environmental contamination of blood cultures by Candida is exceptional.
Candida is the commonest fungal cause of bloodstream infection and ranks among the leading causes of healthcare associated bloodstream infection. Crude mortality is 30 to 40 percent, and attributable mortality is about 15 to 25 percent. Mortality rises where central venous catheters are retained, effective therapy is delayed beyond 24 to 48 hours, or septic shock is present.
Most episodes arise from the patient's own gut flora after mucosal breach, or from skin flora and hospital hands colonising an intravascular device.
| Species | Typical share of candidaemia | Where it dominates | Key features |
|---|---|---|---|
| Candida albicans | 40 to 50 percent and falling | Everywhere, most in community onset and surgical patients | Usually azole and echinocandin susceptible |
| Candida glabrata complex | 20 to 30 percent | North America, northern Europe, older adults, diabetes, azole exposure | Fluconazole susceptible dose dependent or resistant; echinocandin resistance through FKS mutations, often with azole resistance |
| Candida parapsilosis | 15 to 25 percent | Southern Europe, Latin America, Asia, neonates, parenteral nutrition, catheter related disease | Biofilm on catheters and hand carriage; higher echinocandin MICs, usually still susceptible; fluconazole resistant outbreaks occur |
| Candida tropicalis | 5 to 15 percent | Asia, Latin America, haematological malignancy, neutropenia | Aggressive gut translocation; azole resistance is rising |
| Candida krusei (Pichia kudriavzevii) | 2 to 3 percent | Haematological malignancy, fluconazole prophylaxis | Intrinsically fluconazole resistant |
| Candida auris | Variable, outbreak driven | Intensive care, long term care, ventilator units on all continents | Multidrug resistant, persists on skin and surfaces, and spreads between patients |
| Candida lusitaniae | Under 2 percent | Haematological malignancy, intensive care | Can develop amphotericin B resistance during therapy |
| Candida guilliermondii, Candida dubliniensis, Candida kefyr, Candida famata | Under 3 percent combined | Sporadic | Reduced echinocandin susceptibility in Candida guilliermondii |
Incidence varies by setting. Population incidence is roughly 2 to 14 per 100 000 per year in high income countries, and rates in intensive care units are many times higher. Neonates below 1000 g, patients with haematological malignancy, abdominal surgery patients, and patients on parenteral nutrition carry the highest per patient risk. Low and middle income settings have higher shares of Candida parapsilosis and Candida tropicalis, and poor access to blood culture, echinocandins, and susceptibility testing.
Three routes lead to the bloodstream:
- Translocation through the gut wall (the commonest, driven by mucosal injury, bacterial dysbiosis, and neutropenia).
- Colonisation and biofilm on intravascular devices (central venous catheters, haemodialysis catheters, and pacemaker leads).
- Direct inoculation through contaminated infusates or surgery.
Biofilm formation on catheter surfaces, hyphal invasion, and adhesin expression (the ALS adhesin family and HWP1) underlie device infection and are linked to resistance to azoles and amphotericin B.
| Risk factor | Notes |
|---|---|
| Central venous catheter, haemodialysis catheter | Biofilm source; most common modifiable factor |
| Broad spectrum antibacterials | Remove bacterial competition and raise fungal gut burden |
| Parenteral nutrition | Lipid and glucose rich infusate supports growth; catheter dependence |
| Abdominal surgery, anastomotic leak, recurrent perforation, necrotising pancreatitis | Peritoneal inoculation and gut translocation |
| Intensive care stay longer than 7 days, mechanical ventilation, renal replacement therapy | Cumulative device and drug exposure |
| Neutropenia and haematological malignancy, haematopoietic stem cell transplant | Gut mucositis and loss of phagocytic control |
| Solid organ transplant (liver, small bowel, pancreas) | Immunosuppression and surgical breach |
| Multifocal Candida colonisation | Colonisation index above 0.5 in surgical intensive care patients |
| Diabetes mellitus, corticosteroids, burns | Impaired neutrophil function and skin breach |
| Prematurity, very low birth weight, previous azole exposure | Neonatal vulnerability |
| Prior azole exposure | Selects Candida glabrata and Candida krusei |
| Injection drug use | Candidaemia, endophthalmitis, and endocarditis; contaminated preparations |
The Candida score (Leon) is a bedside tool in non neutropenic intensive care patients: parenteral nutrition 1 point, surgery on admission 1, multifocal colonisation 1, and severe sepsis 2.
A score of 3 or more identifies patients at increased risk and has been used to select empirical therapy. However, a randomised trial of empirical micafungin in intensive care patients selected by risk did not improve fungal infection free survival. Empirical therapy is therefore reserved for patients with septic shock and several risk factors, no other explanation, and ideally supportive non culture evidence.
Presentation is non specific. Fever unresponsive to broad spectrum antibacterials is the commonest sign, with hypotension, tachycardia, and organ dysfunction in septic shock. Candidaemia can be indistinguishable from bacterial sepsis, and about 10 to 20 percent of patients have no fever.
Features that raise suspicion include:
- Fever persisting after 3 to 5 days of appropriate antibacterial therapy in a patient with risk factors.
- Erythematous or pustular skin lesions, which are more common with Candida tropicalis in neutropenic patients, and are biopsied for histology and culture.
- Ophthalmic signs: floaters, blurred vision, or white fluffy chorioretinal lesions on fundoscopy.
- Muscle pain in neutropenic patients (tropicalis) and, rarely, a macronodular rash.
- Persistent positive cultures or relapse after catheter retention.
Complications include endophthalmitis (in about 1 to 3 percent of candidaemia and chorioretinitis in up to 10 percent), endocarditis, osteoarticular disease, central nervous system disease, hepatosplenic disease after neutrophil recovery, and metastatic abscesses.
| Condition | Points that separate it |
|---|---|
| Gram negative or Gram positive bacteraemia | Positive bacterial cultures; fungal cultures negative |
| Catheter related bloodstream infection with coagulase negative staphylococci | Catheter tip and paired culture; no yeast |
| Disseminated cryptococcosis, histoplasmosis, or Talaromyces marneffei infection | Antigen testing and specific culture; endemic exposure or advanced HIV |
| Invasive aspergillosis and mucormycosis | Galactomannan, imaging, and tissue histology; mould in culture |
| Infective endocarditis of bacterial cause | Vegetation with negative fungal cultures |
| Pancreatitis with infected necrosis | Imaging guided aspiration; bacterial and fungal cultures |
| Adrenal insufficiency, pulmonary embolism, drug fever in an intensive care patient | Clinical context and absent microbiology |
Blood culture is the reference test. Sensitivity is about 50 to 70 percent for invasive candidiasis, because deep tissue disease and low colony counts in blood can give negative cultures.
Automated systems detect yeast in 24 to 48 hours for most species, and Candida glabrata may need 72 hours or longer. Two or more sets drawn before antifungal therapy, with adequate volume (20 to 30 mL per adult set), improve yield. Fungal blood culture bottles or the lysis centrifugation system add little over standard aerobic bottles for Candida.
Rapid identification. Matrix assisted laser desorption ionisation time of flight mass spectrometry identifies yeast from positive broth or from a subculture. Direct from bottle multiplex panels (peptide nucleic acid fluorescence in situ hybridisation, and multiplex polymerase chain reaction) identify the common species in 1 to 3 hours and, in some panels, detect resistance genes.
A germ tube positive yeast at 3 hours in serum at 37 degrees Celsius is presumptively Candida albicans or Candida dubliniensis. Chromogenic media separate Candida albicans, Candida tropicalis, and Candida krusei on colour. Any non albicans isolate from blood must be identified to species level, because therapy depends on species.
Non culture tests.
| Test | Characteristics | Limitations |
|---|---|---|
| 1,3 beta D glucan | Positive at 80 pg per mL or above in the usual assay (60 to 79 is indeterminate); sensitivity about 75 to 80 percent and specificity about 80 percent for invasive candidiasis; negative predictive value is high | False positives from haemodialysis with cellulose membranes, intravenous immunoglobulin and albumin, gauze or surgical sponges, some antibacterials, and bacteraemia; not specific to Candida and not useful for cryptococcosis or mucormycosis |
| T2 magnetic resonance panel | Direct from whole blood in 3 to 5 hours; sensitivity about 90 percent at 1 colony per mL; detects Candida albicans and Candida tropicalis, Candida parapsilosis, and Candida glabrata with Candida krusei | Limited species coverage; excludes Candida auris in older panels; requires dedicated equipment |
| Mannan antigen with anti mannan antibody | Combined sensitivity near 83 percent with specificity near 86 percent | Variable availability; antibody response is delayed in immunocompromised patients |
| Candida polymerase chain reaction | Increased sensitivity over culture in some series | Not standardised; mostly research or reference laboratory use |
Susceptibility testing is done on every blood isolate, with broth microdilution reference methods or commercial methods, interpreted by species specific breakpoints.
Reference points used for Candida albicans, Candida tropicalis, and Candida parapsilosis are fluconazole susceptible at 2 micrograms per mL or less and resistant at 8 or more. For Candida glabrata, susceptible dose dependent at 32 or less and resistant at 64 or more.
Echinocandin breakpoints are species and agent specific. Micafungin breakpoints for Candida glabrata are 0.06 micrograms per mL or less (susceptible) and 0.25 or more (resistant). FKS1 and FKS2 hot spot sequencing is used when phenotype and clinical response disagree.
Provisional breakpoints for Candida auris from public health agencies are fluconazole 32 micrograms per mL or more, amphotericin B 2 micrograms per mL or more, caspofungin 2 or more, and anidulafungin or micafungin 4 or more, indicating resistance. These values are laboratory thresholds to confirm against the current standard used locally.
Other tests in confirmed candidaemia.
- Repeat blood cultures daily or on alternate days until the first negative.
- Dilated fundoscopy by an ophthalmologist within the first week (and after neutrophil recovery in neutropenic patients).
- Echocardiography (transoesophageal where bloodstream clearance is delayed or a prosthesis is present).
- Abdominal imaging when persistent fever follows clearance.
- Tissue or fluid culture from drained collections.
- Remove or replace the central venous catheter as early as feasible, ideally within 24 hours of the first positive culture, because catheter retention prolongs candidaemia and is linked to higher mortality. Catheter retention is acceptable only where removal is impossible, and therapy is then lengthened.
- Start antifungal therapy promptly, and aim to give the first effective dose within 24 hours of a positive blood culture, with an echinocandin as first line for most adults.
- Search for metastatic foci with dilated fundoscopy, echocardiography and abdominal imaging.
- Treat for 14 days after the first negative blood culture and resolution of symptoms, provided there is no metastatic infection, and with a longer course when deep foci are present.
- De-escalate to oral fluconazole when the isolate is susceptible, the patient is clinically stable, cultures are negative, and gut absorption is reliable, usually after 5 to 7 days of intravenous echinocandin.
Adults, non neutropenic
| Agent | Dose | Notes |
|---|---|---|
| Caspofungin | 70 mg intravenously on day 1, then 50 mg once daily; reduce the maintenance dose to 35 mg daily in moderate hepatic impairment | First line |
| Micafungin | 100 mg intravenously once daily (150 mg daily has been given, with no proven benefit over 100 mg) | First line |
| Anidulafungin | 200 mg intravenously on day 1, then 100 mg once daily | First line; no dose change in renal or hepatic impairment |
| Rezafungin | 400 mg intravenously on day 1, then 200 mg once weekly, for up to 4 weekly doses | Long acting echinocandin; non inferior to caspofungin for candidaemia and invasive candidiasis in a randomised trial; useful for outpatient completion |
| Fluconazole | 800 mg (12 mg per kg) loading dose, then 400 mg (6 mg per kg) once daily, intravenous or oral | For stable patients with susceptible isolates and no recent azole exposure; halve the dose when creatinine clearance is below 50 mL per minute |
| Liposomal amphotericin B | 3 to 5 mg per kg once daily | Where echinocandins or azoles are unsuitable, including some resistant isolates; renal function, potassium, and magnesium monitored |
| Amphotericin B deoxycholate | 0.5 to 1 mg per kg once daily | Reserved for settings with no alternatives; nephrotoxic |
| Voriconazole | 400 mg (6 mg per kg) every 12 hours for 2 doses, then 200 mg (3 mg per kg) every 12 hours | Step down option for Candida krusei or voriconazole susceptible Candida glabrata after clearance; level monitoring |
Species directed therapy
| Species | Preferred therapy | Notes |
|---|---|---|
| Candida albicans, Candida tropicalis | Echinocandin, step down to fluconazole after clearance if susceptible | Routine |
| Candida parapsilosis | Fluconazole 800 mg loading then 400 mg daily, or liposomal amphotericin B | Echinocandins can be used and are acceptable if the patient is already improving; fluconazole is preferred in catheter related disease and neonates |
| Candida glabrata | Echinocandin; step down to high dose fluconazole 800 mg (12 mg per kg) daily only if susceptible dose dependent isolates are confirmed, or to voriconazole | Avoid fluconazole when resistant; use liposomal amphotericin B if echinocandin resistance is shown |
| Candida krusei | Echinocandin, or liposomal amphotericin B, or voriconazole | Intrinsically fluconazole resistant |
| Candida lusitaniae | Echinocandin or fluconazole | Avoid amphotericin B because of acquired resistance |
| Candida auris | Echinocandin first line; liposomal amphotericin B 5 mg per kg once daily for pan echinocandin resistance or non response, or combination therapy in refractory disease | Isolate the patient, apply contact precautions, screen contacts, and clean with sporicidal or chlorine based disinfectants rather than quaternary ammonium agents alone |
Neutropenic patients
An echinocandin or liposomal amphotericin B is first line. Fluconazole is an alternative only in stable patients without prior azole exposure. Therapy continues for 14 days after clearance and until neutropenia has resolved, with ophthalmology review after count recovery. Granulocyte colony stimulating factor is considered when the neutrophil count is low and the infection is severe, with limited evidence.
Neonates and children
| Agent | Neonates | Children above 1 month |
|---|---|---|
| Fluconazole | 12 mg per kg once daily (loading 25 mg per kg in some protocols); adjust for gestational age and renal function | 12 mg per kg once daily (maximum 800 mg daily) |
| Amphotericin B deoxycholate | 1 mg per kg once daily | 1 mg per kg once daily |
| Liposomal amphotericin B | 3 to 5 mg per kg once daily; limited renal penetration in neonates | 3 to 5 mg per kg once daily |
| Micafungin | 10 mg per kg once daily in neonates, as central nervous system penetration is needed | 2 mg per kg once daily (maximum 100 mg) |
| Caspofungin | 25 mg per m2 once daily | 70 mg per m2 on day 1, then 50 mg per m2 once daily |
| Anidulafungin | Limited data | 3 mg per kg on day 1, then 1.5 mg per kg once daily |
All neonates have lumbar puncture, dilated retinal examination, and abdominal and cardiac imaging to find disseminated foci, because central nervous system involvement is frequent in prematurity. Treatment lasts 14 days after the first negative culture in the absence of foci, and for meningitis a minimum of 4 weeks and until resolution of cerebrospinal fluid and imaging abnormalities.
Duration and follow up
- Uncomplicated candidaemia: 14 days from the first negative blood culture and resolution of symptoms.
- Persistent candidaemia beyond 72 hours: search for an undrained focus, retained device, endocarditis, or thrombophlebitis, and extend therapy.
- Septic thrombophlebitis of a peripheral vein: catheter removal and treatment for at least 14 days after culture clearance, longer if thrombosis persists, with surgical excision in selected cases.
- Candidaemia complicated by endophthalmitis, endocarditis, osteoarticular disease, or central nervous system disease: a course of weeks to months, determined by the site.
Adverse effects and monitoring
Echinocandins cause infusion reactions, transaminase elevation, and phlebitis; caspofungin interacts with ciclosporin. Fluconazole prolongs the QT interval and is a CYP2C9 and CYP3A4 inhibitor. Liposomal amphotericin B causes infusion reactions, nephrotoxicity, hypokalaemia, and hypomagnesaemia. Voriconazole causes visual and hepatic toxicity, and trough levels of 1 to 5.5 micrograms per mL are targeted. Liver tests and renal function are checked at baseline and at least weekly.
Empirical, pre emptive, and prophylactic therapy
- Empirical therapy is considered in intensive care patients with septic shock, several risk factors, and persisting fever with no other cause, with an echinocandin and blood cultures taken first, and reviewed at 72 hours.
- Pre emptive therapy guided by beta D glucan or T2 results has been used in high risk patients, with limited randomised evidence.
- Prophylaxis is used in selected groups:
- Fluconazole 3 to 6 mg per kg twice weekly for 6 weeks in neonates below 1000 g (units with candidaemia rates above 10 percent).
- Fluconazole 400 mg daily in high risk abdominal surgery with recurrent perforation or anastomotic leak.
- Fluconazole 400 mg daily or posaconazole 300 mg daily in haematopoietic stem cell transplant and acute leukaemia.
- Fluconazole 400 mg daily in high risk liver transplant recipients.
Prevention rests on aseptic central line insertion and removal of unneeded lines, catheter care bundles, hand hygiene, antibacterial stewardship, early enteral feeding, and prompt surgical source control. For Candida auris, screening of contacts and transferred patients, isolation or cohorting, contact precautions, dedicated equipment, and environmental cleaning with sporicidal or chlorine based agents are required, and outbreaks demand reporting.
