- Intra-abdominal candidiasis
- Candida pneumonia?
- Questions & discussion
candida in the ICU
- Most cultures of Candida represent colonization (e.g., in the urine or especially in the sputum). Thus, there is a major risk of overtreating candidiasis. However, candida does occasionally cause severe invasive infections which should be treated aggressively.
- The approach to Candida is based primarily upon the site where it is isolated and the clinical context.
classification of candidiasis
- If Candida is cultured from a patient, the question is always how to classify this positive culture:
- (1) Colonization (e.g., most cultures from sputum and urine).
- (2) Invasive candidiasis:
- (2a) Candidemia without deep-seated or visceral involvement (e.g., central line infection).
- (2b) Deep-seated or visceral involvement without candidemia (e.g., abdominal abscess).
- (2c) Candidemia plus deep-seated or visceral involvement (e.g., abdominal abscess seeding the blood, or candidemia leading to metastatic infection of other organs).
general risk factors for invasive candidiasis include:
- (1) General patient characteristics:
- Immunosuppression (neutropenia, malignancy, organ transplant, steroid, diabetes).
- (2) Acquisition of candidal colonization:
- Broad-spectrum antibiotics.
- Patients in ICU >1 week.
- Known colonization (e.g., culture of Candida from multiple sites).
- (3) Violation of anatomic barriers:
- Abdominal surgery, GI perforation, anastomotic leak, necrotizing pancreatitis.
- Long-term indwelling catheters (especially hemodialysis and TPN).
- Mucositis due to chemotherapy.
the swinging pendulum of approaches to candidemia
- Candidemia is a relatively indolent process which doesn't tend to cause prompt development of septic shock.
- In the 1970's-1990's, the need to treat candidemia was debated (because the infection didn't seem too aggressive, and the only antifungal therapy available at the time was amphotericin – which is relatively toxic). It was only in the early 1990's that it became accepted wisdom that candidemia required therapy in non-neutropenic patients.(31585478)
- Subsequently, perhaps related to the influence of the Surviving Sepsis Guidelines, there was an increasing stress on early treatment of candidemia. This spawned the practice of preemptive or empiric therapy for patients with possible candidemia.
- However, multiple RCTs investigating the concept of preemptive or empiric therapy for Candida have not found any benefit from this practice.(27706483, 18626047, 24550378, 33044240, 26270686) For example, the EMPIRICUS trial found no benefit from empiric micafungin among critically ill patients with nosocomial sepsis and multiple sites of Candida colonization.(27706483) Meanwhile, resistant Candida is increasingly becoming a problem (likely due to the widespread empiric use of antifungals). Consequently, we now seem to be swinging away from the preemptive therapy. Hopefully the pendulum will wind up somewhere in the middle (e.g., promptly treating known candidemia, without empirically blanketing swaths of ICU patients with antifungal coverage).
- Since Candida is predominantly a nosocomial pathogen, resistance can rapidly become a major problem (because there is a relatively small pool of Candida organisms within the hospital). Several studies have shown marked increases in resistant Candida within less than a decade. We only have a few drugs which are effective against Candida, and if used indiscriminately they will rapidly become ineffective.
clinical manifestations of candidemia
- Fever which is refractory to antibacterial therapy (although this is obviously nonspecific).(31585478)
- Skin lesions may occur, most commonly erythematous papules with pale, vesicular centers(figure above). These may progress to necrotic plaques and tense hemorrhagic bullae.(30102951)
- 💡 Punch biopsy can be used to establish the diagnosis.
ocular involvement is rare
- Endophthalmitis is extremely rare. This involves inflammation of the entire eye (figure below).
- Chorioretinitis is rare, potentially causing visual changes and photosensitivity. For an intubated or obtunded patient, detection requires a dilated eye examination.
diagnosis of candidemia
- Blood culture is not extremely sensitive for candidemia.
- ⚠️ Even a single blood culture positive for “yeast” or Candida should be assumed to represent candidemia and immediately treated as such.
(1-3)-beta-D-glucan assay (BDG)
- This is a serum assay for a cell wall component of several fungi (including Candida, Aspergillus, Pneumocystis, Fusarium, Trichosporon). This may seem nonspecific, but among ICU patients the only nosocomial fungal infections which are commonly associated with BDG positivity are Candida spp., Pneumocystis spp., or Aspergillus spp.(31585478) These can generally be differentiated based on the clinical context, especially chest imaging:
- The sensitivity and specificity of BDG for candidemia are ~80% (with lower performance for focal intra-abdominal infections). This makes BDG potentially useful in septic ICU patients with suspected candidemia. However, if BDG is broadly applied to patients with low pretest probability of Candida infection, it will lead to a high rate of false-positive results.(29376927)
- Using a cutoff value >80 pg/mL may improve sensitivity, potentially yielding the best overall test performance.
- Using a cutoff value >200-250 pg/mL will improve specificity.
- False-positive BDG results may be caused by heavy colonization with Candida or mold, hemodialysis, albumin infusions, blood product administration, and cellulose dressings.(33044240)
investigation after diagnosis of candidemia
Follow-up cultures daily or every-other-day to determine clearance. This will determine the duration of antibiotic therapy.
- Risk factors for candidal endocarditis may include the following:(33044240)
- IV drug use.
- Persistently positive blood cultures over several days, despite antibiotic therapy.
- Intracardiac hardware (prosthetic heart valves, pacemakers).
- Structurally abnormal heart valves (e.g., prior endocarditis).
- New symptoms of heart failure or heart block, or embolic phenomena.
- Overall, the rate of endocarditis is ~3-4%.(30911804) It's debatable whether all patients with candidemia require an echocardiography.(33044240) Overall, transthoracic echocardiography seems reasonable given that this procedure is safe and a positive result will substantially affect management. However, transesophageal echocardiography should probably be used selectively (e.g., for patients at higher risk – especially if transthoracic images are poor).
dilated opthalmologic examination
- Ophthalmologic examination has historically been recommended, although there is no scientific evidence to support this practice:(33044240)
- (1) Dilated eye examinations may overdiagnose candida chorioretinitis among patients with nonspecific chorioretinitis. Modern studies report an incidence of endophthalmitis of <1%, in contrast with older studies.(30998819)
- (2) Medical management of candidemia should be adequate to treat the endophthalmitis, so diagnosing endophthalmitis is unlikely to improve outcomes. Echinocandins don't penetrate the eye optimally, but nonetheless seem to perform adequate clinically. Invasive treatments for endophthalmitis (e.g., vitrectomy or intraocular antibiotic injections) seem to be dangerous and not evidence-based.
- Ophthalmology consultation appears unnecessary for patients who are asymptomatic:(30998819)
treatment of candidemia
hardware removal & source control
- Central lines and other hardware should be removed.
- Any focal sites of infection should be debrided or drained, if possible.
- If the source of candidal infection is unknown, consider CT imaging of the abdomen and pelvis to exclude potential foci of infection (e.g., urinary tract obstruction or gastrointestinal pathology).
antibiotics: initial therapy
- Echinocandins (caspofungin, micafungin, or anidulafungin) are preferred front-line agents for candidemia in the ICU (due to a broad spectrum of activity, excellent tolerance, few drug-drug interactions, fungicidal activity, and anti-biofilm activity).
- All echinocandins have similar efficacy, so selection usually depends on which medication is available at any specific hospital.
- More on echinocandins here.
- If echinocandins are not tolerated or unavailable, a second-line option for broad-spectrum Candida coverage might be an expanded-spectrum azole (with the best evidentiary support for voriconazole).(16243088) Amphotericin is another option that is effective, at the cost of substantially greater toxicity.
de-escalation to an azole, if susceptible
- After the Candida species is known, antifungal therapy may be stepped down to fluconazole if the species is sensitive to it (table above).
- Some centers might be capable of performing sensitivity testing with the patient's own fungal culture. However, most hospitals rely on species identification alone to determine which antifungal agent to use.
- ⚠️ Echinocandins are more potent (especially for biofilms), so de-escalation is recommended only after the patient has clinically stabilized (usually after five or more days of therapy and clearance of Candida from the blood).(32990778) Additionally, de-escalation should not be performed if there is residual intravascular hardware, such as indwelling central lines.(30911804)
duration of therapy
- Uncomplicated candidemia:
- This is defined as an absence of disseminated diseases, abscesses, or endocarditis.
- Treatment should extend for 14 days after the first negative blood culture.
- Candidal endocarditis or deep-seated infections (e.g., abdominal abscesses) may require longer or more complex antibiotic regimens. This is beyond the scope of this chapter; consider consulting with infectious disease and surgeons.
- Candida may occur in the context of polymicrobial intra-abdominal infections (e.g., following bowel perforation, anastomotic leaks, or necrotizing pancreatitis).
- Often this involves abscess formation or peritonitis.
- Blood cultures are generally negative (e.g., with sensitivity of ~20%).
- Beta-D-glucan has better sensitivity than blood cultures, but remains far from perfect (~65%).
- Culturing Candida from abdominal drains doesn't prove invasive infection, as this may simply reflect colonization.
- Culture of purulent material may have the greatest yield, if possible (e.g., surgically or percutaneously).
- For patients diagnosed with candidal intra-abdominal infection (e.g., based on positive cultures), antifungal therapy is indicated. This is the same as therapy for candidemia (e.g., typically beginning with an echinocandin and subsequently stepping down to an azole; more on this above).
- Drainage or debridement of infected tissue is often essential (source control). In particular, echinocandins may not penetrate intra-abdominal abscesses well – so ongoing antibiotic therapy without debridement could merely select out drug-resistant organisms.
- Candida isolated from the sputum almost invariably represents colonization rather than infection.
- True Candidal pneumonia is exceedingly rare:
- This occurs in profoundly immunosuppressed patients, due to hematogenous spread to the lungs.
- Imaging shows multiple pulmonary nodules
- A policy of not reporting Candida in respiratory samples was associated with reduced cost and length of stay – highlighting that overtreatment of respiratory cultures can be detrimental.(14662955)
- Candiduria may occur via one of two routes
- (1) Ascending infection localized to the bladder – this is more common and of little importance. In the absence of surgery or urinary tract obstruction, ascending infection is unlikely to progress further (e.g., into the blood).
- (2) Descending infection that results from candidemia – this is less common, but critically important (because it reflects disseminated candidemia).
- Urine cultures should generally be avoided in ICU patients who have a functional Foley catheter (discussed further in the chapter on catheter-associated urinary tract infections) This will avoid the overdiagnosis of both bacterial and candidal urinary tract “infections.”
- Examine for the presence of costovertebral tenderness (although this may be difficult among ICU patients).
- Urinalysis showing casts composed of candidal elements indicates pyelonephritis.
- An absence of leukocytes in urine argues against invasive infection, but the presence of leukocytes is nonspecific.
- Blood cultures to evaluate for candidemia are not necessary for all patients with candiduria. These should be performed if there is clinical concern regarding possible candidemia (e.g., persistent fevers, sepsis).
- Renal ultrasonography may be considered if there is concern regarding the possibility of obstruction or renal abscess (e.g., persistent candiduria, history of urologic obstruction, or diabetes).
- Serum beta-D-glucan level might be useful to evaluate for systemic involvement. However, colonization may lead to mildly elevated levels, so care is required when interpreting this test.
- In the absence of surgery, candiduria is unlikely to progress to candidemia. Therefore, systemic antimicrobial therapy generally isn't needed. The only indications for antimicrobial therapy would be:
- Neutropenia: treat with an echinocandin as per candidemia above.
- Pending urologic surgery: treat with fluconazole 400 mg daily.
- Changing the Foley catheter is recommended (or removing it).
symptomatic Candida cystitis and/or pyelonephritis
- 🦓 Note: In the absence of urinary obstruction or profound immunosuppression, this would be a rare occurrence in the ICU. Prior to reaching this diagnosis, consider other diagnostic possibilities.
- Urologic interventions:
- Changing the Foley catheter is recommended.
- Consider removal or replacement of nephrostomy tubes or stents.
- Elimination of urinary tract obstruction, if present.
- Antibiotic therapy:
- Echinocandins and liposomal amphotericin aren't useful for urinary tract infection due to poor urinary penetration.
- Fluconazole-susceptible organisms: oral fluconazole 200-400 mg/day, for two weeks.
- Candida glabrata:
- For cystitis: AmB deoxycholate 0.3-0.6 mg/kg daily for 1-7 days, or oral flucytosine 25 mg/kg q6hr x7-10 days.
- For pyelonephritis: AmB deoxycholate 0.3-0.6 mg/kg daily for 1-7 days with or without oral flucytosine 25 mg/kg q6hr.
- Candida krusei: AmB deoxycholate 0.3-0.6 mg/kg daily for 1-7 days.
Follow us on iTunes
The Podcast Episode
Want to Download the Episode?
Right Click Here and Choose Save-As
questions & discussion
To keep this page small and fast, questions & discussion about this post can be found on another page here.
- If blood cultures are positive for yeast, do not delay therapy while waiting for an infectious disease consultation.
- Ensure prompt removal of any hardware (e.g., central lines) if there is evidence of candidemia.
- Avoid treating patients who are colonized with Candida in the urine or sputum.
- EMPIRICUS trial, TheBottomLine review by Segun Olusanya.
- 14662955 Barenfanger J, Arakere P, Cruz RD, et al. Improved outcomes associated with limiting identification of Candida spp. in respiratory secretions. J Clin Microbiol. 2003 Dec;41(12):5645-9. doi: 10.1128/jcm.41.12.5645-5649.2003 [PubMed]
- 16243088 Kullberg BJ, Sobel JD, Ruhnke M, et al. Voriconazole versus a regimen of amphotericin B followed by fluconazole for candidaemia in non-neutropenic patients: a randomised non-inferiority trial. Lancet. 2005 Oct 22-28;366(9495):1435-42. doi: 10.1016/S0140-6736(05)67490-9 [PubMed]
- 18626047 Schuster MG, Edwards JE Jr, Sobel JD, et al. Empirical fluconazole versus placebo for intensive care unit patients: a randomized trial. Ann Intern Med. 2008 Jul 15;149(2):83-90. doi: 10.7326/0003-4819-149-2-200807150-00004 [PubMed]
- 24550378 Ostrosky-Zeichner L, Shoham S, Vazquez J, et al. MSG-01: A randomized, double-blind, placebo-controlled trial of caspofungin prophylaxis followed by preemptive therapy for invasive candidiasis in high-risk adults in the critical care setting. Clin Infect Dis. 2014 May;58(9):1219-26. doi: 10.1093/cid/ciu074 [PubMed]
- 26270686 Knitsch W, Vincent JL, Utzolino S, et al. A randomized, placebo-controlled trial of preemptive antifungal therapy for the prevention of invasive candidiasis following gastrointestinal surgery for intra-abdominal infections. Clin Infect Dis. 2015 Dec 1;61(11):1671-8. doi: 10.1093/cid/civ707 [PubMed]
- 26679628 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 Feb 15;62(4):e1-50. doi: 10.1093/cid/civ933 [PubMed]
- 27706483 Timsit JF, Azoulay E, Schwebel C, et al; EMPIRICUS Trial Group. Empirical Micafungin Treatment and Survival Without Invasive Fungal Infection in Adults With ICU-Acquired Sepsis, Candida Colonization, and Multiple Organ Failure: The EMPIRICUS Randomized Clinical Trial. JAMA. 2016 Oct 18;316(15):1555-1564. doi: 10.1001/jama.2016.14655 [PubMed]
- 29376927 Clancy CJ, Shields RK, Nguyen MH. Invasive Candidiasis in Various Patient Populations: Incorporating Non-Culture Diagnostic Tests into Rational Management Strategies. J Fungi (Basel). 2016 Feb 6;2(1):10. doi: 10.3390/jof2010010 [PubMed]
- 30102951 Shields BE, Rosenbach M, Brown-Joel Z, Berger AP, Ford BA, Wanat KA. Angioinvasive fungal infections impacting the skin: Background, epidemiology, and clinical presentation. J Am Acad Dermatol. 2019 Apr;80(4):869-880.e5. doi: 10.1016/j.jaad.2018.04.059 [PubMed]
- 30911804 Martin-Loeches I, Antonelli M, Cuenca-Estrella M, et al. ESICM/ESCMID task force on practical management of invasive candidiasis in critically ill patients. Intensive Care Med. 2019 Jun;45(6):789-805. doi: 10.1007/s00134-019-05599-w [PubMed]
- 30998819 Breazzano MP, Day HR Jr, Bloch KC, et al. Utility of Ophthalmologic Screening for Patients With Candida Bloodstream Infections: A Systematic Review. JAMA Ophthalmol. 2019 Jun 1;137(6):698-710. doi: 10.1001/jamaophthalmol.2019.0733 [PubMed]
- 31585478 Bassetti M, Giacobbe DR, Vena A, Wolff M. Diagnosis and Treatment of Candidemia in the Intensive Care Unit. Semin Respir Crit Care Med. 2019 Aug;40(4):524-539. doi: 10.1055/s-0039-1693704 [PubMed]
- 32000280 Gonzalez-Lara MF, Ostrosky-Zeichner L. Invasive Candidiasis. Semin Respir Crit Care Med. 2020 Feb;41(1):3-12. doi: 10.1055/s-0040-1701215 [PubMed]
- 32990778 Logan C, Martin-Loeches I, Bicanic T. Invasive candidiasis in critical care: challenges and future directions. Intensive Care Med. 2020 Nov;46(11):2001-2014. doi: 10.1007/s00134-020-06240-x [PubMed]
- 33044240 Peçanha-Pietrobom PM, Colombo AL. Mind the gaps: challenges in the clinical management of invasive candidiasis in critically ill patients. Curr Opin Infect Dis. 2020 Dec;33(6):441-448. doi: 10.1097/QCO.0000000000000684 [PubMed]